EP2542549B1 - Inhibiteurs de glutaminyl cyclase - Google Patents

Inhibiteurs de glutaminyl cyclase Download PDF

Info

Publication number
EP2542549B1
EP2542549B1 EP11707395.7A EP11707395A EP2542549B1 EP 2542549 B1 EP2542549 B1 EP 2542549B1 EP 11707395 A EP11707395 A EP 11707395A EP 2542549 B1 EP2542549 B1 EP 2542549B1
Authority
EP
European Patent Office
Prior art keywords
benzo
imidazole
triazol
compound
thiadiazol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP11707395.7A
Other languages
German (de)
English (en)
Other versions
EP2542549A2 (fr
Inventor
Ulrich Heiser
Daniel Ramsbeck
Torsten Hoffmann
Livia Boehme
Hans-Ulrich Demuth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vivoryon Therapeutics AG
Original Assignee
Probiodrug AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Probiodrug AG filed Critical Probiodrug AG
Publication of EP2542549A2 publication Critical patent/EP2542549A2/fr
Application granted granted Critical
Publication of EP2542549B1 publication Critical patent/EP2542549B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to novel heterocyclic derivatives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5).
  • QC catalyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (5-oxo-prolyl, pGlu*) under liberation of ammonia and the intramolecular cyclization of N-terminal glutamate residues into pyroglutamic acid under liberation of water.
  • Glutaminyl cyclase catalyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (pGlu*) liberating ammonia.
  • pGlu* pyroglutamic acid
  • Inhibitors of QC are described in WO 2004/098625 , WO 2004/098591 , WO 2005/039548 , WO 2005/075436 , WO 2008/055945 , WO 2008/055947 , WO 2008/055950 and WO2008/065141 .
  • EP 02 011 349.4 discloses polynucleotides encoding insect glutaminyl cyclase, as well as polypeptides encoded thereby and their use in methods of screening for agents that reduce glutaminyl cyclase activity. Such agents are useful as pesticides.
  • k i or "K l” and “K D” are binding constants, which describe the binding of an inhibitor to and the subsequent release from an enzyme. Another measure is the “IC 50 " value, which reflects the inhibitor concentration, which at a given substrate concentration results in 50 % enzyme activity.
  • DP IV-inhibitor or "dipeptidyl peptidase IV inhibitor” is generally known to a person skilled in the art and means enzyme inhibitors, which inhibit the catalytic activity of DP IV or DP IV-like enzymes.
  • DP IV-activity is defined as the catalytic activity of dipeptidyl peptidase IV (DP IV) and DP IV-like enzymes. These enzymes are post-proline (to a lesser extent post-alanine, post-serine or post-glycine) cleaving serine proteases found in various tissues of the body of a mammal including kidney, liver, and intestine, where they remove dipeptides from the N-terminus of biologically active peptides with a high specificity when proline or alanine form the residues that are adjacent to the N-terminal amino acid in their sequence.
  • PEP-inhibitor or "prolyl endopeptidase inhibitor” is generally known to a person skilled in the art and means enzyme inhibitors, which inhibit the catalytic activity of prolyl endopeptidase (PEP, prolyl oligopeptidase, POP).
  • PEP-activity is defined as the catalytic activity of an endoprotease that is capable to hydrolyze post proline bonds in peptides or proteins where the proline is in amino acid position 3 or higher counted from the N-terminus of a peptide or protein substrate.
  • QC as used herein comprises glutaminyl cyclase (QC) and QC-like enzymes.
  • QC and QC-like enzymes have identical or similar enzymatic activity, further defined as QC activity.
  • QC-like enzymes can fundamentally differ in their molecular structure from QC.
  • QC-like enzymes are the glutaminyl-peptide cyclotransferase-like proteins (QPCTLs) from human (GenBank NM_017659), mouse (GenBank BC058181), Macaca fascicularis (GenBank AB168255), Macaca mulatta (GenBank XM_001110995), Canis familiaris (GenBank XM_541552), Rattus norvegicus (GenBank XM_001066591), Mus musculus (GenBank BC058181) and Bos taurus (GenBank BT026254).
  • QPCTLs glutaminyl-peptide cyclotransferase-like proteins
  • QC activity is defined as intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (pGlu*) or of N-terminal L-homoglutamine or L- ⁇ -homoglutamine to a cyclic pyro-homoglutamine derivative under liberation of ammonia. See therefore schemes 1 and 2.
  • EC as used herein comprises the activity of QC and QC-like enzymes as glutamate cyclase (EC), further defined as EC activity.
  • EC activity as used herein is defined as intramolecular cyclization of N-terminal glutamate residues into pyroglutamic acid (pGlu*) by QC. See therefore scheme 3.
  • QC-inhibitor "glutaminyl cyclase inhibitor” is generally known to a person skilled in the art and means enzyme inhibitors, which inhibit the catalytic activity of glutaminyl cyclase (QC) or its glutamyl cyclase (EC) activity.
  • the subject method and medical use utilize an agent with an IC 50 for QC inhibition of 10 ⁇ M or less, more preferably of 1 ⁇ M or less, even more preferably of 0.1 ⁇ M or less or 0.01 ⁇ M or less, or most preferably 0.001 ⁇ M or less.
  • an agent with an IC 50 for QC inhibition of 10 ⁇ M or less, more preferably of 1 ⁇ M or less, even more preferably of 0.1 ⁇ M or less or 0.01 ⁇ M or less, or most preferably 0.001 ⁇ M or less.
  • inhibitors with K i values in the lower micromolar, preferably the nanomolar and even more preferably the picomolar range are contemplated.
  • active agents are described herein, for convenience, as "QC inhibitors", it will be understood that such nomenclature is not intending to limit the subject of the invention to a particular mechanism of action.
  • the QC inhibitors of the subject method or medical use will be small molecules, e.g., with molecular weights of 500 g/mole or less, 400 g/mole or less, preferably of 350 g/mole or less, and even more preferably of 300 g/mole or less and even of 250 g/mole or less.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • the term “pharmaceutically acceptable” embraces both human and veterinary use:
  • pharmaceutically acceptable embraces a veterinarily acceptable compound or a compound acceptable in human medicine and health care.
  • alkyl denotes a C 1-12 alkyl group, suitably a C 1-8 alkyl group, e.g. C 1-6 alkyl group, e.g. C 1-4 alkyl group.
  • Alkyl groups may be straight chain or branched. Suitable alkyl groups include, for example, methyl, ethyl, propyl (e.g. n-propyl and isopropyl), butyl (e.g n-butyl, iso-butyl, sec-butyl and tert-butyl), pentyl (e.g. n-pentyl), hexyl (e.g.
  • alk for example in the expressions "alkoxy”, "haloalkyl” and “thioalkyl” should be interpreted in accordance with the definition of "alkyl”.
  • alkoxy groups include methoxy, ethoxy, propoxy (e.g. n-propoxy), butoxy (e.g. n-butoxy), pentoxy (e.g. n-pentoxy), hexoxy (e.g. n-hexoxy), heptoxy (e.g.
  • n-heptoxy n-heptoxy
  • octoxy e.g. n-octoxy
  • exemplary thioalkyl groups include methylthio-.
  • exemplary haloalkyl groups include fluoroalkyl e.g. CF 3 .
  • alkenyl denotes a C 2-12 alkenyl group, suitably a C 2-6 alkenyl group, e.g. a C 2-4 alkenyl group, which contains at least one double bond at any desired location and which does not contain any triple bonds.
  • Alkenyl groups may be straight chain or branched.
  • Exemplary alkenyl groups including one double bond include propenyl and butenyl.
  • Exemplary alkenyl groups including two double bonds include pentadienyl, e.g. (1 E, 3E)-pentadienyl.
  • alkynyl denotes a C 2-12 alkynyl group, suitably a C 2-6 alkynyl group, e.g. a C 2-4 alkynyl group, which contains at least one triple bond at any desired location and may or may not also contain one or more double bonds.
  • Alkynyl groups may be straight chain or branched.
  • Exemplary alkynyl groups include propynyl and butynyl.
  • alkylene denotes a chain of formula -(CH 2 ) n - wherein n is an integer e.g. 2-5, unless specifically limited.
  • cycloalkyl denotes a C 3-10 cycloalkyl group (i.e. 3 to 10 ring carbon atoms), more suitably a C 3-8 cycloalkyl group, e.g. a C 3-6 cycloalkyl group.
  • exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • a most suitable number of ring carbon atoms is three to six.
  • cycloalkenyl denotes a C 5-10 cycloalkenyl group (i.e. 5 to 10 ring carbon atoms), more suitably a C 5-8 cycloalkenyl group e.g. a C 5-6 cycloalkenyl group.
  • exemplary cycloalkenyl groups include cyclopropenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • a most suitable number of ring carbon atoms is five to six.
  • Carbocyclyl denotes any ring system in which all the ring atoms are carbon and which contains between three and twelve ring carbon atoms, suitably between three and ten carbon atoms and more suitably between three and eight carbon atoms.
  • Carbocyclyl groups may be saturated or partially unsaturated, but do not include aromatic rings. Examples of carbocyclyl groups include monocyclic, bicyclic, and tricyclic ring systems, in particular monocyclic and bicyclic ring systems. Other carbocylcyl groups include bridged ring systems (e.g. bicyclo[2.2.1]heptenyl).
  • a specific example of a carbocyclyl group is a cycloalkyl group. A further example of a carbocyclyl group is a cycloalkenyl group.
  • heterocyclyl refers to a carbocyclyl group wherein one or more (e.g. 1, 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O.
  • a specific example of a heterocyclyl group is a cycloalkyl group (e.g. cyclopentyl or more particularly cyclohexyl) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S or O.
  • heterocyclyl groups containing one hetero atom include pyrrolidine, tetrahydrofuran and piperidine, and exemplary heterocyclyl groups containing two hetero atoms include morpholine, piperazine, dioxolane and dioxane.
  • a further specific example of a heterocyclyl group is a cycloalkenyl group (e.g. a cyclohexenyl group) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S and O.
  • An example of such a group is dihydropyranyl (e.g. 3,4-dihydro-2H-pyran-2-yl-).
  • aryl denotes a C 6-12 aryl group, suitably a C 6-10 aryl group, more suitably a C 6-8 aryl group.
  • Aryl groups will contain at least one aromatic ring (e.g. one, two or three rings).
  • An example of a typical aryl group with one aromatic ring is phenyl.
  • An example of a typical aryl group with two aromatic rings is naphthyl.
  • heteroaryl denotes an aryl residue, wherein one or more (e.g. 1, 2, 3, or 4, suitably 1, 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O, or else a 5-membered aromatic ring containing one or more (e.g. 1,2,3, or 4, suitably 1, 2 or 3) ring atoms selected from N, S and O.
  • exemplary monocyclic heteroaryl groups having one heteroatom include: five membered rings (e.g. pyrrole, furan, thiophene); and six membered rings (e.g.
  • pyridine such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl
  • exemplary monocyclic heteroaryl groups having two heteroatoms include: five membered rings (e.g. pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, such as imidazol-1-yl, imidazol-2-yl imidazol-4-yl); six membered rings (e.g. pyridazine, pyrimidine, pyrazine).
  • Exemplary monocyclic heteroaryl groups having three heteroatoms include: 1,2,3-triazole and 1,2,4-triazole.
  • Exemplary monocyclic heteroaryl groups having four heteroatoms include tetrazole.
  • Exemplary bicyclic heteroaryl groups include: indole (e.g. indol-6-yl), benzofuran, benzthiophene, quinoline, isoquinoline, indazole, benzimidazole, benzthiazole, quinazoline and purine.
  • alkylaryl unless specifically limited, denotes an aryl residue which is connected via an alkylene moiety e.g. a C 1-4 alkylene moiety.
  • alkylheteroaryl unless specifically limited, denotes a heteroaryl residue which is connected via an alkylene moiety e.g. a C 1-4 alkylene moiety.
  • halogen or “halo” comprises fluorine (F), chlorine (Cl) and bromine (Br).
  • amino refers to the group -NH 2 .
  • phenyl substituted by phenyl refers to biphenyl.
  • benzimidazol-5-yl which is represented as:
  • benzimidazol-6-yl which is represented as: is an equivalent structure.
  • the two forms of benzimidazolyl are covered by the term "benzimidazol-5-yl".
  • the processes for the preparation of the compounds according to the invention give rise to a mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • Salts and solvates of the compounds of formula (I) and physiologically functional derivatives thereof which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable.
  • salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds and their pharmaceutically acceptable salts and solvates.
  • Suitable salts according to the invention include those formed with both organic and inorganic acids or bases.
  • Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulfuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulfamic, sulfanilic, succinic, oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic, oxaloacetic, methanesulfonic, ethanesulfonic, arylsulfonic (for example p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic or naphthalenedisulfonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl
  • Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexylamine and N -methyl-D-glucamine. All pharmaceutically acceptable acid addition salt forms of the compounds of the present invention are intended to be embraced by the scope of this invention.
  • some of the crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the present invention discloses prodrugs of the compounds of this invention.
  • such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound.
  • the term “administering” shall encompass the treatment of the various disorders described with prodrug versions of one or more of the claimed compounds, but which converts to the above specified compound in vivo after administration to the subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in " Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985 .
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973 ; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 .
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • composition is intended to encompass a product comprising the claimed compounds in the therapeutically effective amounts, as well as any product which results, directly or indirectly, from combinations of the claimed compounds.
  • suitable carriers and additives may advantageously include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Carriers which can be added to the mixture, include necessary and inert pharmaceutical excipients, including, but not limited to, suitable binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, coatings, disintegrating agents, dyes and coloring agents.
  • Soluble polymers as targetable drug carriers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolyllysine substituted with palmitoyl residue.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • carbocyclyl and heterocyclyl When carbocyclyl and heterocyclyl are substituted, they are typically substituted by 1 or 2 substituents (e.g. 1 substitent). Typically the substituent is methyl. More typically carbocyclyl and heterocyclyl groups are unsubstituted.
  • aryl and heteroaryl When aryl and heteroaryl are substituted, they are typically substituted by 1, 2 or 3 (e.g. 1 or 2) substituents.
  • Substituents for aryl and heteroaryl are selected from C 1-6 alkyl (e.g. methyl), C 2-6 alkenyl (e.g. buten-3-yl), C 2-6 alkynyl (e.g. butyn-3-yl), C 1-6 haloalkyl (e.g. fluoromethyl, trifluoromethyl), -C 1-6 thioalkyl (e.g. -S-methyl), -SOC 1-4 alkyl (e.g. -SOmethyl), -SO 2 C 1-4 alkyl (e.g.
  • -SO 2 methyl C 1-6 alkoxy- (e.g. methoxy, ethoxy), -O-C 3-8 cycloalkyl (e.g. -O-cyclopentyl), C 3-8 cycloalkyl (e.g. cyclopropyl, cyclohexyl), -SO 2 C 3-8 cycloalkyl (e.g. -SO 2 cyclohexyl), -SOC 3-6 cycloalkyl (e.g. -SOcyclopropyl), C 3-6 alkenyloxy- (e.g. -O-buten-2-yl), C 3-6 alkynyloxy- (e.g.
  • -O-buten-2-yl -C(O)C 1-6 alkyl (e.g. -C(O)ethyl), -C(O)OC 1-6 alkyl (e.g. -C(O)O-methyl), C 1-6 alkoxy-C 1-6 alkyl- (e.g. methoxy-ethyl-), nitro, halogen (e.g. fluoro, chloro, bromo), cyano, hydroxyl,-C(O)OH, -NH 2 , -NHC 1-4 alkyl (e.g. -NHmethyl), -N(C 1-4 alkyl)(C 1-4 alkyl) (e.g.
  • substituents will be selected from C 1-6 alkyl (e.g. methyl), C 1-6 haloalkyl (e.g. C 1-6 fluoroalkyl, e.g. CF 3 ), C 1-6 alkoxy (e.g. OMe), halogen and hydroxy.
  • R 1 represents heteroaryl
  • examples include monocyclic (e.g. 5 and 6 membered) and bicyclic (e.g. 9 and 10 membered, particularly 9 membered) heteroaryl rings, especially rings containing nitrogen atoms (e.g. 1 or 2 nitrogen atoms).
  • a suitable bicyclic heteroaryl ring is a 9-membered heteroaryl ring containing 1 or 2 nitrogen atoms, especially a benzene ring fused to a 5-membered ring containing one or two nitrogen atoms (e.g. 1 H-benzoimidazolyl). Most suitably the point of attachment is through a benzene ring, e.g. the group is 1 H-benzoimidazol-5-yl.
  • heteroaryl groups may either be unsubstituted (which is more typical) or may suitably be substituted by one or more (e.g. 1 or 2) substituents selected from alkyl (e.g. C 1-4 alkyl such as Me), alkoxy- (e.g. C 1-4 alkoxy- such as OMe) and halogen (e.g. F).
  • alkyl e.g. C 1-4 alkyl such as Me
  • alkoxy- e.g. C 1-4 alkoxy- such as OMe
  • halogen e.g. F
  • R 1 heteroaryl groups include a 9-membered bicyclic ring containing 2 nitrogen atoms, which ring may optionally be substituted, for example:
  • examples include:
  • an example includes:
  • examples include:
  • Y represents triazol-one
  • an example includes:
  • Y represents triazol-thione
  • an example includes:
  • aryl may typically represent phenyl.
  • exemplary substituted phenyl groups include 3-methylphenyl-, 2,3-dichlorophenyl-, 2,3-difluorophenyl-, 2,4-dichlorophenyl-, 2,4-difluororophenyl-, 2,4-dimethoxyphenyl-, 2,4-dimethylphenyl-, 2,4-bis(trifluoromethyl)phenyl-, 2,4,6-trifluorophenyl-, 2,4,6-trimethylphenyl-, 2,6-dichlorophenyl-, 2,6-difluorophenyl-, 2,6-dimethoxyphenyl-, 2,6-difluoro-4-(methoxy)phenyl-, 2-isopropyl-6-methylphenyl-, 3-(cyclopentyloxy)-4-methoxyphenyl-, 3,4,5-trimethoxyphenyl-
  • R 2 may represent unsubstituted phenyl-.
  • substituted phenyl groups include 2,3,4-trifluorophenyl, 2,3-difluoro-4-methylphenyl, 2-bromo-4-fluorophenyl-, 2-bromo-5-fluorophenyl-, 2-chlorophenyl-, 2-fluorophenyl-, 2-fluoro-5-(trifluoromethyl)phenyl-, 2-hydroxy-3-methoxyphenyl-, 2-hydroxy-5-methylphenyl-, 3-chlorophenyl-, 3-fluorophenyl-, 3-fluoro-4-(trifluoromethyl)phenyl-, 3-fluoro-5-(trifluoromethyl)phenyl-, 2-fluoro-4-(trifluoromethyl)phenyl-, 3-fluoro-4-(methoxy)phenyl-, 3-hydroxy-4-methoxyphenyl-, 4-bromo-2-fluorophenyl
  • R 2 represents optionally substituted aryl and aryl represents naphthyl
  • examples include unsubstituted naphthyl (e.g. naphthalen-1-yl, naphthalen-2-yl, naphthalen-3-yl) as well as substituted naphthyl (e.g. 4-methyl-naphthalen-2-yl-, 5-methyl-naphthalen-3-yl-, 7-methyl-naphthalen-3-y- and 4-fluoro-naphthalen-2-yl-).
  • unsubstituted naphthyl e.g. naphthalen-1-yl, naphthalen-2-yl, naphthalen-3-yl
  • substituted naphthyl e.g. 4-methyl-naphthalen-2-yl-, 5-methyl-naphthalen-3-yl-, 7-methyl-naphthalen-3-y- and 4-fluoro-naphthalen-2-yl-
  • R 2 represents optionally substituted heteroaryl
  • examples include monocyclic rings (e.g. 5 or 6 membered rings) and bicyclic rings (e.g. 9 or 10 membered rings) which may optionally be substituted.
  • Example 5 membered rings include pyrrolyl (e.g. pyrrol-2-yl) and imidazolyl (e.g. 1 H-imidazol-2-yl or 1 H-imidazol-4-yl), pyrazolyl (e.g. 1 H-pyrazol-3-yl), furanyl (e.g. furan-2-yl), thiazolyl (e.g. thiazol-2-yl), thiophenyl (e.g.
  • Example 6 membered rings include pyridinyl (e.g. pyridin-2-yl and pyridin-4-yl). Specific substituents that may be mentioned are one or more e.g. 1, 2 or 3 groups selected from halogen, hydroxyl, alkyl (e.g. methyl) and alkoxy- (e.g. methoxy-).
  • Example substituted 5 membered rings include 4,5-dimethyl-furan-2-yl-, 5-hydroxymethyl-furan-2-yl-, 5-methyl-furan-2-yl- and 6-methyl-pyridin-2-yl-.
  • An example substituted 6-membered ring is 1-oxy-pyridin-4-yl-.
  • Example 9 membered rings include 1 H-indolyl (e.g. 1 H-indol-3-yl, 1 H-indol-5-yl), benzothiophenyl (e.g. benzo[b]thiophen-3-yl, particularly 2-benzo[b]thiophen-3-yl), benzo[1,2,5]-oxadiazolyl (e.g. benzo[1,2,5]-oxadiazol-5-yl), benzo[1,2,5]-thiadiazolyl (e.g. benzo[1,2,5]-thiadiazol-5-yl, benzo[1,2,5]thiadiazol-6-yl).
  • 1 H-indolyl e.g. 1 H-indol-3-yl, 1 H-indol-5-yl
  • benzothiophenyl e.g. benzo[b]thiophen
  • Example 10 membered rings include quinolinyl (e.g.quinolin-3-yl, quinolin-4-yl, quinolin-8-yl). Specific substituents that may be mentioned are one or more e.g. 1, 2 or 3 groups selected from halogen, hydroxyl, alkyl (e.g. methyl) and alkoxy- (e.g. methoxy-).
  • Example substituted 9-membered rings include 1-methyl-1 H-indol-3-yl, 2-methyl-1 H-indol-3-yl, 6-methyl-1H-indol-3-yl.
  • Example substituted 10 membered rings include 2-chloro-quinolin-3-yl, 8-hydroxy-quinolin-2-yl, oxo-chromenyl (e.g. 4-oxo-4H-chromen-3-yl) and 6-methyl-4-oxo-4H-chromen-3-yl.
  • oxo-chromenyl e.g. 4-oxo-4H-chromen-3-yl
  • 6-methyl-4-oxo-4H-chromen-3-yl 6-methyl-4-oxo-4H-chromen-3-yl.
  • R 2 represents carbocyclyl
  • examples include cycloalkyl and cycloalkenyl.
  • examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Examples of cycloalkenyl include cyclohexenyl (e.g. cyclohex-2-enyl, cyclohex-3-enyl).
  • substituted carbocyclyl examples include 2-methyl-cyclohexyl-, 3-methyl-cyclohexyl-, 4-methyl-cyclohexyl-, 2-methyl-cyclohex-2-enyl, 2-methyl-cyclohex-3-enyl, 3-methyl-cyclohex-3-enyl, 3-methyl-cyclohex-3-enyl.
  • R 2 represents phenyl substituted by phenyl or phenyl substituted by a monocyclic heteroaryl group, in which any of aforesaid phenyl and heteroaryl groups may optionally be substituted, typically the phenyl ring connected directly to the nitrogen atom is unsubstituted and the terminal phenyl ring or the monocyclic heteroaryl ring is optionally substituted by one, two or three substitutents (e.g. one or two, e.g. one). Typically the terminal phenyl or monocyclic heteroaryl group is unsubstituted. Typically the terminal phenyl or monocyclic heteroaryl group substitutes the other phenyl group at the 4-position.
  • R 2 represents phenyl substituted by phenyl in which any of aforesaid phenyl groups may optionally be substituted, examples include -biphenyl-4-yl.
  • R 2 represents phenyl substituted by a monocyclic C 6-12 heteroaryl group, in which any of aforesaid phenyl and heteroaryl groups may optionally be substituted, examples include 4-(oxazol-5-yl)phenyl-.
  • R 2 represents phenyl substituted by benzyloxy in which any of aforesaid phenyl and benzyloxy groups may optionally be substituted
  • examples include 4-benzyloxy-phenyl-, 4-(3-methylbenzyloxy)phenyl- and 4-(4-methylbenzyloxy)phenyl-.
  • R 2 represents optionally substituted phenyl fused to optionally substituted C 3-12 carbocyclyl
  • examples include indanyl (e.g. indan-4-yl-, 2-methyl-indan-4-yl-), indenyl and tetralinyl.
  • R 2 represents optionally substituted phenyl fused to optionally substituted C 3-12 heterocyclyl
  • examples include benzo[1,3]dioxo-4-yl- and 2,3-dihydro-benzo[1,4]dioxin-4-yl-.
  • R 1 represents a phenyl ring fused with a 5 membered heteroaryl ring containing one or more (e.g. one or two, suitably one, more suitably two) nitrogen atoms or a pyridine ring fused with a 5-membered heteroaryl ring containing one or more (e.g. one or two, suitably one, more suitably two) nitrogen atoms.
  • R 1 represents bicyclic heteroaryl, preferably the heteroaryl group does not contain S atoms.
  • R 1 represents a phenyl ring fused to a 5-membered heteroaryl ring, preferably R 1 is linked to the core of formula (I) through the phenyl ring.
  • R 1 represents a pyridine ring fused to a 5-membered heteroaryl ring, preferably R 1 is linked to the core of formula (I) through the pyridine ring.
  • R 1 represents unsubstituted heteroaryl.
  • R 1 suitably represents 1 H-benzoimidazolyl or imidazo[1,2-a]pyridine, particularly 1 H-benzoimidazolyl, especially 1 H-benzoimidazol-5-yl.
  • R 1 represents wherein R 14 represents H and R 15 represents H.
  • B represents a bond
  • R 1 represents wherein R 16 represents H and R 17 represents H.
  • C represents a bond
  • R 1 represents wherein R 18 represents H and R 19 represents H.
  • D represents a bond
  • R 1 represents
  • R 1 represents
  • Y represents triazolyl or thiadiazolyl.
  • Y is attached to R 1 via a carbon atom.
  • Y represents triazolyl, such as:
  • Y represents thiadiazolyl.
  • Y represents thiadiazolyl, such as: 1,3,4-thiadiazolyl, i.e.
  • Y represents thiazolyl.
  • Y represents thiazolyl, such as:
  • Y represents triazol-one, such as:
  • Y represents triazol-thione, such as: 4H-1,2,4-triazol-3-thione, i.e.
  • X represents a linker selected from -(CH 2 ) m -R 2 , -(CH 2 ) p -S-R 2 , -(CH 2 ) p -O-R 2 or-(CH 2 ) p -SO 2 -R 2 .
  • X represents a linker selected from -(CH 2 ) m -R 2 and -(CH 2 ) p -S-R 2 (i.e. -CH 2 -R 2 , (CH 2 ) 2 -R 2 or -CH 2 -S-R 2 ).
  • X represents -(CH 2 ) m -R 2 .
  • X represents -CH 2 -R 2 , -(CH 2 ) 2 -R 2 or -(CH 2 ) 3 -R 2 .
  • X represents -CH 2 -R 2 or -(CH 2 ) 2 -R 2 .
  • X represents -CH 2 -R 2 .
  • X represents -(CH 2 ) 2 -R 2 ⁇
  • X represents -(CH 2 ) n -S-R 2 .
  • X represents -CH 2 -S-R 2 .
  • X represents -(CH 2 ) p -O-R 2 In one embodiment, X represents -CH 2 -O-R 2 .
  • X represents -(CH 2 ) p -SO 2 -R 2 .
  • X represents -CH 2 -SO 2 -R 2 .
  • n represents an integer selected from 1 to 3. In a further embodiment, m represents an integer selected from 1 or 2.
  • n 1
  • p represents the integer 1.
  • R 2 represents C 6-12 aryl, C 6-12 heteroaryl, C 3-12 carbocyclyl, phenyl substituted by phenoxy or phenyl fused to C 3-12 heterocyclyl. More suitably, R 2 represents C 6-12 aryl, C 3-12 heteroaryl, phenyl substituted by phenoxy or phenyl fused to C 3-12 heterocyclyl. Yet more suitably, R 2 represents optionally substituted C 6-12 aryl or phenyl substituted by phenoxy. Still yet more suitably, R 2 represents optionally substituted C 6-12 aryl.
  • R 2 represents C 3-12 carbocyclyl.
  • R 2 suitably represents cyclohexyl.
  • R 2 represents optionally substituted C 6-12 aryl.
  • R 2 suitably represents optionally substituted phenyl or napthyl. More suitably, R 2 represents optionally substituted phenyl.
  • R 2 represents phenyl optionally substituted by one or more groups selected from C 1-6 alkyl (e.g. methyl), C 1-6 alkoxy (e.g. methoxy or ethoxy), -C 1-6 thioalkyl (e.g. methylthio), haloC 1-6 alkyl (e.g. trifluoromethyl), haloC 1-6 alkoxy (e.g. trifluoromethoxy) or halogen (e.g. chlorine or fluorine).
  • R 2 represents phenyl optionally substituted by one or more groups selected from C 1-6 alkoxy (e.g. methoxy) or halogen (e.g. chlorine).
  • R 2 represents optionally substituted phenyl
  • R 2 suitably represents 2-methylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 5-trifluoromethylphenyl, 2,5-bis(trifluoromethyl), 4-methylthio(phenyl), 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-ethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4
  • R 2 represents optionally substituted C 6-12 heteroaryl.
  • R 2 suitably represents optionally substituted pyridyl.
  • R 2 represents unsubstituted pyridyl, e.g. pyridin-4-yl.
  • R 2 represents phenyl substituted by phenyl, the aforesaid phenyl groups optionally being substituted.
  • R 2 suitably represents phenyl substituted by 3-phenyl, phenyl substituted by 4-phenyl, phenyl substituted by 3-(3-chlorophenyl), phenyl substituted by 4-(3-chlorophenyl), phenyl substituted by 4-(3,4-dichlorophenyl) or 3-fluorophenyl substituted by 4-phenyl.
  • R 2 represents optionally substituted phenyl substituted by optionally substituted phenoxy.
  • R 2 suitably represents phenyl substituted by 4-phenoxy.
  • R 2 represents optionally substituted phenyl substituted by optionally substituted heterocyclyl.
  • R 2 represents optionally substituted phenyl substituted by optionally substituted heterocyclyl
  • R 2 suitably represents 3-chlorophenyl substituted by 4-morpholinyl, phenyl substituted by 4-piperazinyl substituted by 4N-methyl, phenyl substituted by 4-piperazinyl substituted by 4N-phenyl, phenyl substituted by 3-piperazinyl substituted by 4N-phenyl or 2-chlorophenyl substituted by 6-piperazinyl substituted by 4N-ethyl.
  • R 2 represents optionally substituted phenyl substituted by -O-C 1-4 alkyl-C 3-12 heterocyclyl.
  • R 2 suitably represents phenyl substituted by 4-O-(CH 2 ) 2 -morpholinyl, 4-O-(CH 2 ) 3 -morpholinyl, 2-O-(CH 2 ) 2 -morpholinyl or 4-O-(CH 2 ) 2 -piperazinyl.
  • R 2 represents optionally substituted phenyl fused to optionally substituted C 3-12 heterocyclyl.
  • R 2 suitably represents benzo-1,3-dioxolanyl, 4-methoxy(benzo-1,3-dioxolanyl), 6-methoxy(benzo-1,3-dioxolanyl), 2,2-difluoro(benzo-1,3-dioxolanyl) or benzo-1,4-dioxanyl.
  • R 2 when R 2 represents optionally substituted phenyl fused to optionally substituted C 3-12 heterocyclyl, R 2 suitably represents benzo-1,3-dioxolanyl.
  • Y represents triazolyl or thiadiazolyl
  • X represents -(CH 2 ) m - and -(CH 2 ) p -S- (i.e. -CH 2 -, (CH 2 ) 2 - or -CH 2 -S-)
  • R 2 represents phenyl optionally substituted by one or more groups selected from C 1-6 alkoxy (e.g. methoxy) or halogen (e.g. chlorine) or R 2 represents phenyl substituted by phenoxy.
  • Novel intermediates are claimed as an aspect of the present invention.
  • Physiological substrates of QC (EC) in mammals are, e.g. amyloid beta-peptides (3-40), (3-42), (11-40 and (11-42), ABri, ADan, Gastrin, Neurotensin, FPP, CCL 2, CCL 7, CCL 8, CCL 16, CCL 18, Fractalkine, Orexin A, [Gln 3 ]-glucagon(3-29), [Gln 5 ]-substance P(5-11) and the peptide QYNAD.
  • Table 1 The compounds and/or combinations according to the present invention and pharmaceutical compositions comprising at least one inhibitor of QC (EC) are useful for the treatment of conditions that can be treated by modulation of QC activity.
  • Table 1 Amino acid sequences of physiological active peptides with an N-terminal glutamine residue, which are prone to be cyclized to final pGlu Peptide
  • Amino acid sequence Function Abeta(1-42) Plays a role in neurodegeneration, e.g. in Alzheimer's Disease, Familial British Dementia, Familial Danish Dementia, Down Syndrome Abeta(1-40) Plays a role in neurodegeneration, e.g. in Alzheimer's Disease, Familial British Dementia, Familial Danish Dementia, Down Syndrome Abeta(3-42) Plays a role in neurodegeneration, e.g.
  • Alzheimer's Disease Familial British Dementia, Familial Danish Dementia, Down Syndrome Abeta(3-40) Plays a role in neurodegeneration, e.g. in Alzheimer's Disease, Familial British Dementia, Familial Danish Dementia, Down Syndrome Abeta(11-42) Plays a role in neurodegeneration, e.g. in Alzheimer's Disease, Familial British Dementia, Familial Danish Dementia, Down Syndrome Abeta(11-40) Plays a role in neurodegeneration, e.g.
  • TRH Swiss-Prot: P20396 QHP amide TRH functions as a regulator of the biosynthesis of TSH in the anterior pituitary gland and as a neurotransmitter/ neuromodulator in the central and peripheral nervous systems.
  • GnRH Swiss-Prot P01148 QHWSYGL RP(G) amide Stimulates the secretion of gonadotropins; it stimulates the secretion of both luteinizing and follicle-stimulating hormones.
  • CCL16 (small inducible cytokine A16) Swiss-Prot: 015467 Shows chemotactic activity for lymphocytes and monocytes but not neutrophils. Also shows potent myelosuppressive activity, suppresses proliferation of myeloid progenitor cells.
  • Recombinant SCYA16 shows chemotactic activity for monocytes and THP-1 monocytes, but not for resting lymphocytes and neutrophils.
  • CCL8 small inducible cytokine A8 Swiss-Prot: P80075 Chemotactic factor that attracts monocytes, lymphocytes, basophils and eosinophils. May play a role in neoplasia and inflammatory host responses. This protein can bind heparin.
  • CCL2 MCP-1, small inducible cytokine A2 Swiss-Prot: P13500 Chemotactic factor that attracts monocytes and basophils but not neutrophils or eosinophils. Augments monocyte anti-tumor activity.
  • naive T lymphocytes toward dendritic cells and activated macrophages in lymph nodes has chemotactic activity for naive T cells, CD4+ and CD8+ T cells and thus may play a role in both humoral and cell-mediated immunity responses.
  • Fractalkine (neurotactin) Swiss-Prot: P78423 The soluble form is chemotactic for T cells and monocytes, but not for neutrophils.
  • the membrane-bound form promotes adhesion of those leukocytes to endothelial cells. May play a role in regulating leukocyte adhesion and migration processes at the endothelium binds to CX3CR1.
  • CCL7 small inducible cytokine A7 Swiss-Prot: P80098 Chemotactic factor that attracts monocytes and eosinophils, but not neutrophils. Augments monocyte anti-tumor activity. Also induces the release of gelatinase B. This protein can bind heparin. Binds to CCR1, CCR2 and CCR3. Orexin A (Hypocretin-1) Swiss-Prot 043612 Neuropeptide that plays a significant role in the regulation of food intake and sleep-wakefulness, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions. It plays also a broader role in the homeostatic regulation of energy metabolism, autonomic function, hormonal balance and the regulation of body fluids.
  • Orexin-A binds to both OX1R and OX2R with a high affinity.
  • Substance P RPK PQQFFGLM Belongs to the tachykinins.
  • Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles.
  • QYNAD Gln-Tyr-Asn-Ala-Asp Acts on voltage-gated sodium channels.
  • Glutamate is found in positions 3, 11 and 22 of the amyloid ⁇ -peptide.
  • the mutation from glutamic acid (E) to glutamine (Q) in position 22 has been described as the so called Dutch type cerebroarterial amyloidosis mutation.
  • the ⁇ -amyloid peptides with a pyroglutamic acid residue in position 3, 11 and/or 22 have been described to be more cytotoxic and hydrophobic than the amyloid ⁇ -peptide 1-40(42/43) ( Saido T.C. 2000 Medical Hypotheses 54(3): 427-429 ).
  • the multiple N-terminal variations, e.g. Abeta(3-40), Abeta(3-42), Abeta(11-40) and Abeta (11-42) can be generated by the ⁇ -secretase enzyme ⁇ -site amyloid precursor protein-cleaving enzyme (BACE) at different sites ( Huse J.T. et al. 2002 J. Biol. Chem.
  • Transepithelial transducing cells particularly the gastrin (G) cell, co-ordinate gastric acid secretion with the arrival of food in the stomach.
  • G gastrin
  • Biosynthetic precursors and intermediates are putative growth factors; their products, the amidated gastrins, regulate epithelial cell proliferation, the differentiation of acid-producing parietal cells and histamine-secreting enterochromaffin-like (ECL) cells, and the expression of genes associated with histamine synthesis and storage in ECL cells, as well as acutely stimulating acid secretion.
  • Gastrin also stimulates the production of members of the epidermal growth factor (EGF) family, which in turn inhibit parietal cell function but stimulate the growth of surface epithelial cells.
  • EGF epidermal growth factor
  • Plasma gastrin concentrations are elevated in subjects with Helicobacterpylori, who are known to have increased risk of duodenal ulcer disease and gastric cancer ( Dockray, G.J. 1999 J Physiol 15 315-324 ).
  • the peptide hormone gastrin released from antral G cells, is known to stimulate the synthesis and release of histamine from ECL cells in the oxyntic mucosa via CCK-2 receptors.
  • the mobilized histamine induces acid secretion by binding to the H(2) receptors located on parietal cells.
  • gastrin in both its fully amidated and less processed forms (progastrin and glycine-extended gastrin), is also a growth factor for the gastrointestinal tract. It has been established that the major trophic effect of amidated gastrin is for the oxyntic mucosa of stomach, where it causes increased proliferation of gastric stem cells and ECL cells, resulting in increased parietal and ECL cell mass.
  • the major trophic target of the less processed gastrin e.g. glycine-extended gastrin
  • the colonic mucosa Koh, T.J. and Chen, D. 2000 Regul Pept 9337-44 .
  • Neurotensin is a neuropeptide implicated in the pathophysiology of schizophrenia that specifically modulates neurotransmitter systems previously demonstrated to be misregulated in this disorder.
  • Clinical studies in which cerebrospinal fluid (CSF) NT concentrations have been measured revealed a subset of schizophrenic patients with decreased CSF NT concentrations that are restored by effective antipsychotic drug treatment.
  • CSF cerebrospinal fluid
  • Considerable evidence also exists concordant with the involvement of NT systems in the mechanism of action of antipsychotic drugs.
  • the behavioral and biochemical effects of centrally administered NT remarkably resemble those of systemically administered antipsychotic drugs, and antipsychotic drugs increase NT neurotransmission. This concatenation of findings led to the hypothesis that NT functions as an endogenous antipsychotic.
  • FPP Fertilization promoting peptide
  • TRH thyrotrophin releasing hormone
  • FPP and adenosine have been shown to stimulate cAMP production in uncapacitated cells but inhibit it in capacitated cells, with FPP receptors somehow interacting with adenosine receptors and G proteins to achieve regulation of AC. These events affect the tyrosine phosphorylation state of various proteins, some being important in the initial "switching on”, others possibly being involved in the acrosome reaction itself.
  • Calcitonin and angiotensin II also found in seminal plasma, have similar effects in vitro on uncapacitated spermatozoa and can augment responses to FPP. These molecules have similar effects in vivo, affecting fertility by stimulating and then maintaining fertilizing potential.
  • CCL2 (MCP-1), CCL7, CCL8, CCL16, CCL18 and fractalkine play an important role in pathophysiological conditions, such as suppression of proliferation of myeloid progenitor cells, neoplasia, inflammatory host responses, cancer, psoriasis, rheumatoid arthritis, atherosclerosis, vasculitis, humoral and cell-mediated immunity responses, leukocyte adhesion and migration processes at the endothelium, inflammatory bowel disease, restenosis, pulmonary fibrosis, pulmonary hypertention, liver fibrosis, liver cirrhosis, nephrosclerosis, ventricular remodeling, heart failure, arteriopathy after organ transplantations and failure of vein grafts.
  • pathophysiological conditions such as suppression of proliferation of myeloid progenitor cells, neoplasia, inflammatory host responses, cancer, psoriasis, rheumatoid arthritis, atherosclerosis, vasculitis, humor
  • pancreatitis Bhatia, M., et al., (2005) Am.JPhysiol Gastrointest.Liver Physiol 288, G1259-G1265 ); Alzheimer's disease ( Yamamoto, M., et al., (2005) Am.J Pathol. 166, 1475-1485 ); lung fibrosis ( Inoshima, I., et al., (2004) Am.J Physiol Lung Cell Mol.Physiol 286, L1038-L1044 ); renal fibrosis ( Wada, T., et al., (2004) J Am.Soc.Nephrol.
  • MCP-1 might also play a role in gestosis ( Katabuchi, H., et al., (2003) Med Electron Microsc. 36, 253-262 ), as a paracrine factor in tumor development ( Ohta, M., et al., (2003) Int.J Oncol. 22, 773-778 ; Li, S., et al., (2005) J Exp.Med 202, 617-624 ), neuropathic pain ( White, F. A., et al., (2005) Proc. Natl.
  • MCP-1 levels are increased in CSF of AD patients and patients showing mild cognitive impairment (MCI) ( Galimberti, D., et al., (2006) Arch.Neurol. 63, 538-543 ). Furthermore, MCP-1 shows an increased level in serum of patients with MCI and early AD ( Clerici, F., et al., (2006) Neurobiol.Aging 27, 1763-1768 ).
  • MCI mild cognitive impairment
  • cytotoxic T lymphocyte peptide-based vaccines against hepatitis B, human immunodeficiency virus and melanoma were recently studied in clinical trials.
  • This peptide is a Melan-A/MART-1 antigen immunodominant peptide analog, with an N-terminal glutamic acid. It has been reported that the amino group and gamma-carboxylic group of glutamic acids, as well as the amino group and gamma-carboxamide group of glutamines, condense easily to form pyroglutamic derivatives.
  • Orexin A is a neuropeptide that plays a significant role in the regulation of food intake and sleep-wakefulness, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions. It plays also a role in the homeostatic regulation of energy metabolism, autonomic function, hormonal balance and the regulation of body fluids.
  • QYNAD is a substrate of the enzyme glutaminyl cyclase (QC, EC 2.3.2.5), which is also present in the brain of mammals, especially in human brain. Glutaminyl cyclase catalyzes effectively the formation of pEYNAD from its precursor QYNAD.
  • the present invention provides the use of the compounds of formula (I) for the preparation of a medicament for the prevention or alleviation or treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome, Huntington's disease, Kennedy's disease, ulcer disease, duodenal cancer with or w/o Helicobacter pylori infections, colorectal cancer, Zolliger-Ellison syndrome, gastric cancer with or without Helicobacter pylori infections, pathogenic psychotic conditions, schizophrenia, infertility, neoplasia, inflammatory host responses, cancer, malign metastasis, melanoma, psoriasis, rheumatoid arthritis, atherosclerosis, pancreatitis, restenosis, impaired humoral and cell-mediated immune responses, impaired food intake, impaired sleep-wakefulness, impaired homeostatic regulation of energy metabolism, impaired autonomic function,
  • a QC inhibitor according to the present invention can lead to suppression of male fertility.
  • the present invention provides the use of inhibitors of QC (EC) activity in combination with other agents, especially for the treatment of neuronal diseases, artherosclerosis and multiple sclerosis.
  • the present invention also provides a method of treatment of the aforementioned diseases comprising the administration of a therapeutically active amount of at least one compound of formula (I) to a mammal, preferably a human.
  • said method and corresponding uses are for the treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome, Parkinson's disease and Chorea Huntington, comprising the administration of a therapeutically active amount of at least one compound of formula (I) to a mammal, preferably a human.
  • a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome, Parkinson's disease and Chorea Huntington, comprising the administration of a therapeutically active amount of at least one compound of formula (I) to a mammal, preferably a human.
  • the present invention provides a method of treatment and corresponding uses for the treatment of rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis.
  • the present invention provides a composition, preferably a pharmaceutical composition, comprising at least one QC inhibitor optionally in combination with at least one other agent selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • at least one QC inhibitor optionally in combination with at least one other agent selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.
  • said QC inhibitor is a compound of formula (I) of the present invention.
  • the aforementioned other agent is selected from the group consisting of beta-amyloid antibodies, cysteine protease inhibitors, PEP-inhibitors, LiCl, acetylcholinesterase (AChE) inhibitors, PIMT enhancers, inhibitors of beta secretases, inhibitors of gamma secretases, inhibitors of aminopeptidases, preferably inhibitors of dipeptidyl peptidases, most preferably DP IV inhibitors; inhibitors of neutral endopeptidase, inhibitors of Phosphodiesterase-4 (PDE-4), TNFalpha inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulatory agents, immunosuppressive agents, MCP-1 antagonists or an agent selected from the group consisting of antegren (natalizumab), Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 57
  • the other agent may be, for example, an anti-anxiety drug or antidepressant selected from the group consisting of
  • the other agent may be, for example, an anti-multiple sclerosis drug selected from the group consisting of
  • compositions e.g. for parenteral, enteral or oral administration, comprising at least one QC inhibitor, optionally in combination with at least one of the other aforementioned agents.
  • the invention provides a method for the treatment of these conditions.
  • the method comprises either co-administration of at least one QC inhibitor and at least one of the other agents or the sequential administration thereof.
  • Co-administration includes administration of a formulation, which comprises at least one QC inhibitor and at least one of the other agents or the essentially simultaneous administration of separate formulations of each agent.
  • Beta-amyloid antibodies and compositions containing the same are described, e.g. in WO 2006/137354 , WO 2006/118959 , WO 2006/103116 , WO 2006/095041 , WO 2006/081171 , WO 2006/066233 , WO 2006/066171 , WO 2006/066089 , WO 2006/066049 , WO 2006/055178 , WO 2006/046644 , WO 2006/039470 , WO 2006/036291 , WO 2006/026408 , WO 2006/016644 , WO 2006/014638 , WO 2006/014478 , WO 2006/008661 , WO 2005/123775 , WO 2005/120571 , WO 2005/105998 , WO 2005/081872 , WO 2005/080435 , WO 2005/028511 , WO 2005/025616 , WO 2005/025516 , WO 2005/
  • the beta-amyloid antibodies may be selected from, for example, polyclonal, monoclonal, chimenic or humanized antibodies. Furthermore, said antibodies may be useful to develop active and passive immune therapies, i.e. vaccines and monoclonal antibodies.
  • Suitable examples of beta-amyloid antibodies are ACU-5A5, huC091 (Acumen/Merck); PF-4360365, RI-1014, RI-1219, RI-409, RN-1219 (Rinat Neuroscience Corp (Pfizer Inc)); the nanobody therapeutics of Ablynx/Boehringer Ingelheim; beta-amyloid-specific humanized monoclonal antibodies of Intellect Neurosciences/IBL; m266, m266.2 (Eli Lilly & Co.); AAB-02 (Elan); bapineuzumab (Elan); BAN-2401 (Bioarctic Neuroscience AB); ABP-102 (Abiogen Pharma SpA); BA-27, BC-05 (Takeda); R-1450
  • antibodies which recognize the N-terminus of the A ⁇ peptide.
  • a suitable antibody which recognizes the A ⁇ -N-Terminus is, for example AcI-24 (AC Immune SA).
  • a monoclonal antibody against beta-amyloid peptide is disclosed in WO 2007/068412 .
  • Respective chimeric and humanized antibodies are disclosed in WO 2008/011348 .
  • a method for producing a vaccine composition for treating an amyloid-associated disease is disclosed in WO 2007/068411 .
  • Suitable cysteine protease inhibitors are inhibitors of cathepsin B.
  • Inhibitors of cathepsin B and compositions containing such inhibitors are described, e.g. in WO 2006/060473 , WO 2006/042103 , WO 2006/039807 , WO 2006/021413 , WO 2006/021409 , WO 2005/097103 , WO 2005/007199 , WO2004/084830 , WO 2004/078908 , WO 2004/026851 , WO 2002/094881 , WO 2002/027418 , WO 2002/021509 , WO 1998/046559 , WO 1996/021655 .
  • PIMT enhancers are 10-aminoaliphatyl-dibenz[b, f] oxepines described in WO 98/15647 and WO 03/057204 , respectively. Further useful according to the present invention are modulators of PIMT activity described in WO 2004/039773 .
  • Inhibitors of beta secretase and compositions containing such inhibitors are described, e.g. in WO03/059346 , WO2006/099352 , WO2006/078576 , WO2006/060109 , WO2006/057983 , WO2006/057945 , WO2006/055434 , WO2006/044497 , WO2006/034296 , WO2006/034277 , WO2006/029850 , WO2006/026204 , WO2006/014944 , WO2006/014762 , WO2006/002004 , US 7,109,217 , WO2005/113484 , WO2005/103043 , WO2005/103020 , WO2005/065195 , WO2005/051914 , WO2005/044830 , WO2005/032471 , WO2005/018545 , WO2005/004803 , WO2005/004802 ,
  • beta secretase inhibitors for the purpose of the present invention are WY-25105 (Wyeth); Posiphen, (+)-phenserine (TorreyPines / NIH); LSN-2434074, LY-2070275, LY-2070273, LY-2070102 (Eli Lilly & Co.); PNU-159775A, PNU-178025A, PNU-17820A, PNU-33312, PNU-38773, PNU-90530 (Elan / Pfizer); KMI-370, KMI-358, kmi-008 (Kyoto University); OM-99-2, OM-003 (Athenagen Inc.); AZ-12304146 (AstraZeneca / Astex); GW-840736X (GlaxoSmith Kline plc.), DNP-004089 (De Novo Pharmaceuticals Ltd.) and CT-21166 (CoMentis Inc.).
  • Inhibitors of gamma secretase and compositions containing such inhibitors are described, e.g. in WO2005/008250 , WO2006/004880 , US 7,122,675 , US 7,030,239 , US 6,992,081 , US 6,982,264 , WO2005/097768 , WO2005/028440 , WO2004/101562 , US 6,756,511 , US 6,683,091 , WO03/066592 , WO03/014075 , WO03/013527 , WO02/36555 , WO01/53255 , US 7,109,217 , US 7,101,895 , US 7,049,296 , US 7,034,182 , US 6,984,626 , WO2005/040126 , WO2005/030731 , WO2005/014553 , US 6,890,956 , EP 1334085 , EP 1263774 ,
  • Suitable gamma secretase inhibitors for the purpose of the present invention are GSI-953, WAY-GSI-A, WAY-GSI-B (Wyeth); MK-0752, MRK-560, L-852505, L-685-458, L-852631, L-852646 (Merck & Co. Inc.); LY-450139, LY-411575, AN-37124 (Eli Lilly & Co.); BMS-299897, BMS-433796 (Bristol-Myers Squibb Co.); E-2012 (Eisai Co. Ltd.); EHT-0206, EHT-206 (ExonHit Therapeutics SA); and NGX-555 (TorreyPines Therapeutics Inc.).
  • DP IV-inhibitors and compositions containing such inhibitors are described, e.g. in US6,011,155 ; US6,107,317 ; US6,110,949 ; US6,124,305 ; US6,172,081 ; WO99/61431 , WO99/67278 , WO99/67279 , DE19834591 , WO97/40832 , WO95/15309 , WO98/19998 , WO00/07617 , WO99/38501 , WO99/46272 , WO99/38501 , WO01/68603 , WO01/40180 , WO01/81337 , WO01/81304 , WO01/55105 , WO02/02560 , WO01/34594 , WO02/38541 , WO02/083128 , WO03/072556 , WO03/002593 , WO03/000250 , WO03/
  • Suitable DP IV-inhibitors for the purpose of the present invention are for example Sitagliptin, des-fluoro-sitagliptin (Merck & Co. Inc.); vildagliptin, DPP-728, SDZ-272-070 (Novartis); ABT-279, ABT-341 (Abbott Laboratories); denagliptin, TA-6666 (GlaxoSmithKline plc.); SYR-322 (Takeda San Diego Inc.); talabostat (Point Therapeutics Inc.); Ro-0730699, R-1499, R-1438 (Roche Holding AG); FE-999011 (Ferring Pharmaceuticals); TS-021 (Taisho Pharmaceutical Co.
  • GRC-8200 (Glenmark Pharmaceuticals Ltd.); ALS-2-0426 (Alantos Pharmaceuticals Holding Inc.); ARI-2243 (Arisaph Pharmaceuticals Inc.); SSR-162369 (Sanofi-Synthelabo); MP-513 (Mitsubishi Pharma Corp.); DP-893, CP-867534-01 (Pfizer Inc.); TSL-225, TMC-2A (Tanabe Seiyaku Co.
  • PHX-1149 Phenomenix Corp.
  • saxagliptin Bristol-Myers Squibb Co.
  • PSN-9301 ((OSI) Prosidion), S-40755 (Servier); KRP-104 (ActivX Biosciences Inc.); sulphostin (Zaidan Hojin); KR-62436 (Korea Research Institute of Chemical Technology); P32/98 (Probiodrug AG); BI-A, BI-B (Boehringer Ingelheim Corp.); SK-0403 (Sanwa Kagaku Kenkyusho Co. Ltd.); and NNC-72-2138 (Novo Nordisk A/S).
  • Suitable beta amyloid synthesis inhibitors for the purpose of the present invention are for example Bisnorcymserine (Axonyx Inc.); (R)-flurbiprofen (MCP-7869; Flurizan) (Myriad Genetics); nitroflurbiprofen (NicOx); BGC-20-0406 (Sankyo Co. Ltd.) and BGC-20-0466 (BTG plc.).
  • Suitable amyloid protein deposition inhibitors for the purpose of the present invention are for example SP-233 (Samaritan Pharmaceuticals); AZD-103 (Ellipsis Neurotherapeutics Inc.); AAB-001 (Bapineuzumab), AAB-002, ACC-001 (Elan Corp plc.); Colostrinin (ReGen Therapeutics plc.); Tramiprosate (Neurochem); AdPEDI-(amyloid-betal-6)11) (Vaxin Inc.); MPI-127585, MPI-423948 (Mayo Foundation); SP-08 (Georgetown University); ACU-5A5 (Acumen / Merck); Transthyretin (State University of New York); PTI-777, DP-74, DP 68, Exebryl (ProteoTech Inc.); m266 (Eli Lilly & Co.); EGb-761 (Dr.
  • Suitable PDE-4 inhibitors for the purpose of the present invention are for example Doxofylline (Instituto Biologico Chemioterapica ABC SpA.); idudilast eye drops, tipelukast, ibudilast (Kyorin Pharmaceutical Co.
  • a preferred PDE-4-inhibitor is Rolipram.
  • MAO inhibitors and compositions containing such inhibitors are described, e.g. in WO2006/091988 , WO2005/007614 , WO2004/089351 , WO01/26656 , WO01/12176 , WO99/57120 , WO99/57119 , WO99/13878 , WO98/40102 , WO98/01157 , WO96/20946 , WO94/07890 and WO92/21333 .
  • Suitable MAO-inhibitors for the purpose of the present invention are for example Linezolid (Pharmacia Corp.); RWJ-416457 (RW Johnson Pharmaceutical Research Institute); budipine (Altana AG); GPX-325 (BioResearch Ireland); isocarboxazid; phenelzine; tranylcypromine; indantadol (Chiesi Farmaceutici SpA.); moclobemide (Roche Holding AG); SL-25.1131 (Sanofi-Synthelabo); CX-1370 (Burroughs Wellcome Co.); CX-157 (Krenitsky Pharmaceuticals Inc.); desoxypeganine (HF Arzneiffenforschung GmbH & Co.
  • Linezolid Pharmacia Corp.
  • RWJ-416457 RW Johnson Pharmaceutical Research Institute
  • budipine Altana AG
  • GPX-325 BioResearch Ireland
  • isocarboxazid phenelzine
  • Suitable histamine H3 antagonists for the purpose of the present invention are, e.g. ABT-239, ABT-834 (Abbott Laboratories); 3874-H1 (Aventis Pharma); UCL-2173 (Berlin Free University), UCL-1470 (BioProjet, Societe Civile de für); DWP-302 (Daewoong Pharmaceutical Co Ltd); GSK-189254A, GSK-207040A (GlaxoSmithKline Inc.); cipralisant, GT-2203 (Gliatech Inc.); Ciproxifan (INSERM), 1S,2S -2-(2-Aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (Hokkaido University); JNJ-17216498, JNJ-5207852 (Johnson & Johnson); NNC-0038-0000-1049 (Novo Nordisk A/S); and Sch-79687 (Schering-Plough).
  • PEP inhibitors and compositions containing such inhibitors are described, e.g. in JP 01042465 , JP 03031298 , JP 04208299 , WO 00/71144 , US 5,847,155 ; JP 09040693 , JP 10077300 , JP 05331072 , JP 05015314 , WO 95/15310 , WO 93/00361 , EP 0556482 , JP 06234693 , JP 01068396 , EP 0709373 , US 5,965,556 , US 5,756,763 , US 6,121,311 , JP 63264454 , JP 64000069 , JP 63162672 , EP 0268190 , EP 0277588 , EP 0275482 , US 4,977,180 , US 5,091,406 , US 4,983,624 , US 5,112,847 , US 5,100,904 , US 5,25
  • Suitable prolyl endopeptidase inhibitors for the purpose of the present invention are, e.g. Fmoc-Ala-Pyrr-CN, Z-Phe-Pro-Benzothiazole (Probiodrug), Z-321 (Zeria Pharmaceutical Co Ltd.); ONO-1603 (Ono Pharmaceutical Co Ltd); JTP-4819 (Japan Tobacco Inc.) and S-17092 (Servier).
  • NPY neuropeptide Y
  • NPY mimetic NPY mimetic
  • NPY agonist or antagonist NPY ligand of the NPY receptors.
  • Preferred according to the present invention are antagonists of the NPY receptors.
  • Suitable ligands or antagonists of the NPY receptors are 3a, 4,5,9b-tetrahydro-1h-benz[e]indol-2-yl amine-derived compounds as disclosed in WO 00/68197 .
  • NPY receptor antagonists which may be mentioned include those disclosed in European patent applications EP 0 614 911 , EP 0 747 357 , EP 0 747 356 and EP 0 747 378 ; international patent applications WO 94/17035 , WO 97/19911 , WO 97/19913 , WO 96/12489 , WO 97/19914 , WO 96/22305 , WO 96/40660 , WO 96/12490 , WO 97/09308 , WO 97/20820 , WO 97/20821 , WO 97/20822 , WO 97/20823 , WO 97/19682 , WO 97/25041 , WO 97/34843 , WO 97/46250 , WO 98/03492 , WO 98/03493 , WO 98/03494 and WO 98/07420 ; WO 00/30674
  • NPY antagonists include those compounds that are specifically disclosed in these patent documents. More preferred compounds include amino acid and non-peptide-based NPY antagonists.
  • Amino acid and non-peptide-based NPY antagonists which may be mentioned include those disclosed in European patent applications EP 0 614 911 , EP 0 747 357 , EP 0 747 356 and EP 0 747 378 ; international patent applications WO 94/17035 , WO 97/19911 , WO 97/19913 , WO 96/12489 , WO 97/19914 , WO 96/22305 , WO 96/40660 , WO 96/12490 , WO 97/09308 , WO 97/20820 , WO 97/20821 , WO 97/20822 , WO 97/20823 , WO 97/19682 , WO 97/25041 , WO 97/34843 , WO 97/46250 , WO 98/03492 , WO 98/03493 , WO 98/03494 , WO 98/07
  • Particularly preferred compounds include amino acid-based NPY antagonists.
  • Amino acid-based compounds which may be mentioned include those disclosed in international patent applications WO 94/17035 , WO 97/19911 , WO 97/19913 , WO 97/19914 or, preferably, WO 99/15498 .
  • Preferred amino acid-based NPY antagonists include those that are specifically disclosed in these patent documents, for example BIBP3226 and, especially, (R)-N2-(diphenylacetyl)-(R)-N-[1-(4-hydroxy- phenyl) ethyl] arginine amide (Example 4 of international patent application WO 99/15498 ).
  • M1 receptor agonists and compositions containing such inhibitors are described, e.g. in WO2004/087158 , WO91/10664 .
  • Suitable M1 receptor antagonists for the purpose of the present invention are for example CDD-0102 (Cognitive Pharmaceuticals); Cevimeline (Evoxac) (Snow Brand Milk Products Co. Ltd.); NGX-267 (TorreyPines Therapeutics); sabcomeline (GlaxoSmithKline); alvameline (H Lundbeck A/S); LY-593093 (Eli Lilly & Co.); VRTX-3 (Vertex Pharmaceuticals Inc.); WAY-132983 (Wyeth) and CI-101 7/ (PD-151832) (Pfizer Inc.).
  • Acetylcholinesterase inhibitors and compositions containing such inhibitors are described, e.g. in WO2006/071274 , WO2006/070394 , WO2006/040688 , WO2005/092009 , WO2005/079789 , WO2005/039580 , WO2005/027975 , WO2004/084884 , WO2004/037234 , WO2004/032929 , WO03/101458 , WO03/091220 , WO03/082820 , WO03/020289 , WO02/32412 , WO01/85145 , WO01/78728 , WO01/66096 , WO00/02549 , WO01/00215 , WO00/15205 , WO00/23057 , WO00/33840 , WO00/30446 , WO00/23057 , WO00/15205 , WO00/09483
  • Suitable acetylcholinesterase inhibitors for the purpose of the present invention are for example Donepezil (Eisai Co. Ltd.); rivastigmine (Novartis AG); (-)-phenserine (TorreyPines Therapeutics); ladostigil (Hebrew University of Jerusalem); huperzine A (Mayo Foundation); galantamine (Johnson & Johnson); Memoquin (Universita di Bologna); SP-004 (Samaritan Pharmaceuticals Inc.); BGC-20-1259 (Sankyo Co.
  • NMDA receptor antagonists and compositions containing such inhibitors are described, e.g. in WO2006/094674 , WO2006/058236 , WO2006/058059 , WO2006/010965 , WO2005/000216 , WO2005/102390 , WO2005/079779 , WO2005/079756 , WO2005/072705 , WO2005/070429 , WO2005/055996 , WO2005/035522 , WO2005/009421 , WO2005/000216 , WO2004/092189 , WO2004/039371 , WO2004/028522 , WO2004/009062 , WO03/010159 , WO02/072542 , WO02/34718 , WO01/98262 , WO01/94321 , WO01/92204 , WO01/81295 , WO01/32640 , WO01/
  • Suitable NMDA receptor antagonists for the purpose of the present invention are for example Memantine (Merz & Co. GmbH); topiramate (Johnson & Johnson); AVP-923 (Neurodex) (Center for Neurologic Study); EN-3231 (Endo Pharmaceuticals Holdings Inc.); neramexane (MRZ-2/579) (Merz and Forest); CNS-5161 (CeNeS Pharmaceuticals Inc.); dexanabinol (HU-211; Sinnabidol; PA-50211) (Pharmos); EpiCept NP-1 (Dalhousie University); indantadol (V-3381; CNP-3381) (Vernalis); perzinfotel (EAA-090, WAY-126090, EAA-129) (Wyeth); RGH-896 (Gedeon Richter Ltd.); traxoprodil (CP-101606), besonprodil (PD-196860, CI-1041) (Pfizer Inc.); CGX-10
  • the present invention relates to combination therapies useful for the treatment of atherosclerosis, restenosis or arthritis, administering a QC inhibitor in combination with another therapeutic agent selected from the group consisting of inhibitors of the angiotensin converting enzyme (ACE); angiotensin II receptor blockers; diuretics; calcium channel blockers (CCB); beta-blockers; platelet aggregation inhibitors; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; high density lipoprotein (HDL) increasing compounds; renin inhibitors; IL-6 inhibitors; antiinflammatory corticosteroids; antiproliferative agents; nitric oxide donors; inhibitors of extracellular matrix synthesis; growth factor or cytokine signal transduction inhibitors; MCP-1 antagonists and tyrosine kinase inhibitors providing beneficial or synergistic therapeutic effects over each monotherapy component alone.
  • ACE angiotensin converting enzyme
  • CB calcium channel blockers
  • beta-blockers beta-blockers
  • Angiotensin II receptor blockers are understood to be those active agents that bind to the AT1 -receptor subtype of angiotensin II receptor but do not result in activation of the receptor. As a consequence of the blockade of the AT1 receptor, these antagonists can, e.g. be employed as antihypertensive agents.
  • Suitable angiotensin II receptor blockers which may be employed in the combination of the present invention include AT 1 receptor antagonists having differing structural features, preferred are those with non-peptidic structures.
  • AT 1 receptor antagonists having differing structural features, preferred are those with non-peptidic structures.
  • Preferred AT1-receptor antagonists are those agents that have been approved and reached the market, most preferred is valsartan, or a pharmaceutically acceptable salt thereof.
  • the interruption of the enzymatic degradation of angiotensin to angiotensin II with ACE inhibitors is a successful variant for the regulation of blood pressure and thus also makes available a therapeutic method for the treatment of hypertension.
  • a suitable ACE inhibitor to be employed in the combination of the present invention is, e.g. a compound selected from the group consisting alacepril, benazepril, benazeprilat; captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril and trandolapril, or in each case, a pharmaceutically acceptable salt thereof.
  • Preferred ACE inhibitors are those agents that have been marketed, most preferred are benazepril and enalapril.
  • a diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylclothiazide, and chlorothalidon.
  • the most preferred diuretic is hydrochlorothiazide.
  • a diuretic furthermore comprises a potassium sparing diuretic such as amiloride or triameterine, or a pharmaceutically acceptable salt thereof.
  • the class of CCBs essentially comprises dihydropyridines (DHPs) and non-DHPs, such as diltiazem-type and verapamil-type CCBs.
  • DHPs dihydropyridines
  • non-DHPs such as diltiazem-type and verapamil-type CCBs.
  • a CCB useful in said combination is preferably a DHP representative selected from the group consisting of amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine and nivaldipine, and is preferably a non-DHP representative selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in each case, a pharmaceutically acceptable salt thereof. All these CCBs are therapeutically used, e.g. as anti-hypertensive, anti-angina pectoris or anti-arrhythmic drugs.
  • Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine and verapamil or, e.g. dependent on the specific CCB, a pharmaceutically acceptable salt thereof.
  • DHP is amlodipine or a pharmaceutically acceptable salt thereof, especially the besylate.
  • An especially preferred representative of non-DHPs is verapamil or a pharmaceutically acceptable salt, especially the hydrochloride, thereof.
  • Beta-blockers suitable for use in the present invention include beta-adrenergic blocking agents (beta-blockers), which compete with epinephrine for beta-adrenergic receptors and interfere with the action of epinephrine.
  • beta-blockers are selective for the beta-adrenergic receptor as compared to the alpha-adrenergic receptors, and so do not have a significant alpha-blocking effect.
  • Suitable beta-blockers include compounds selected from acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol.
  • beta-blocker is an acid or base or otherwise capable of forming pharmaceutically acceptable salts or prodrugs
  • these forms are considered to be encompassed herein, and it is understood that the compounds may be administered in free form or in the form of a pharmaceutically acceptable salt or a prodrug, such as a physiologically hydrolyzable and acceptable ester.
  • a pharmaceutically acceptable salt or a prodrug such as a physiologically hydrolyzable and acceptable ester.
  • metoprolol is suitably administered as its tartrate salt
  • propranolol is suitably administered as the hydrochloride salt, and so forth.
  • Platelet aggregation inhibitors include PLAVIX® (clopidogrel bisulfate), PLETAL® (cilostazol) and aspirin.
  • Cholesterol absorption modulators include ZETIA® (ezetimibe) and KT6-971 (Kotobuki Pharmaceutical Co. Japan).
  • HMG-Co-A reductase inhibitors also called beta-hydroxy-beta-methylglutaryl-co-enzyme-A reductase inhibitors or statins
  • statins are understood to be those active agents which may be used to lower lipid levels including cholesterol in blood.
  • the class of HMG-Co-A reductase inhibitors comprises compounds having differing structural features.
  • the compounds which are selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, or in each case, a pharmaceutically acceptable salt thereof.
  • HMG-Co-A reductase inhibitors are those agents, which have been marketed, most preferred is atorvastatin, pitavastatin or simvastatin, or a pharmaceutically acceptable salt thereof.
  • HDL-increasing compounds include, but are not limited to, cholesterol ester transfer protein (CETP) inhibitors.
  • CETP inhibitors include JTT7O5 disclosed in Example 26 of U.S. Patent No. 6,426,365 issued July 30, 2002 , and pharmaceutically acceptable salts thereof.
  • Interleukin 6 mediated inflammation may be achieved indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion or by direct inhibition of the signal transduction pathway utilizing interleukin-6 inhibitor/antibody, interleukin-6 receptor inhibitor/antibody, interleukin-6 antisense oligonucleotide (ASON), gp130 protein inhibitor/antibody, tyrosine kinase inhibitors/antibodies, serine/threonine kinase inhibitors/antibodies, mitogen-activated protein (MAP) kinase inhibitors/antibodies, phosphatidylinositol 3-kinase (PI3K) inhibitors/antibodies, Nuclear factor kappaB (NF- ⁇ B) inhibitors/antibodies, I ⁇ B kinase (IKK) inhibitors/antibodies, activator protein-1 (AP-1) inhibitors/antibodies, STAT transcription factors inhibitors/antibodies, altered IL-6, partial peptid
  • a suitable antiinflammatory corticosteroid is dexamethasone.
  • Suitable antiproliferative agents are cladribine, rapamycin, vincristine and taxol.
  • a suitable inhibitor of extracellular matrix synthesis is halofuginone.
  • a suitable growth factor or cytokine signal transduction inhibitor is, e.g. the ras inhibitor R115777.
  • a suitable tyrosine kinase inhibitor is tyrphostin.
  • Suitable renin inhibitors are described, e.g. in WO 2006/116435 .
  • a preferred renin inhibitor is aliskiren, preferably in the form of the hemi-fumarate salt thereof.
  • MCP-1 antagonists may, e.g. be selected from anti-MCP-1 antibodies, preferably monoclonal or humanized monoclonal antibodies, MCP-1 expression inhibitors, CCR2-antagonists, TNF-alpha inhibitors, VCAM-1 gene expression inhibitors and anti-C5a monoclonal antibodies.
  • MCP-1 antagonists and compositions containing such inhibitors are described, e.g. in WO02/070509 , WO02/081463 , WO02/060900 , US2006/670364 , US2006/677365 , WO2006/097624 , US2006/316449 , WO2004/056727 , WO03/053368 , WO00/198289 , WO00/157226 , WO00/046195 , WO00/046196 , WO00/046199 , WO00/046198 , WO00/046197 , WO99/046991 , WO99/007351 , WO98/006703 , WO97/012615 , WO2005/105133 , WO03/037376 , WO2006/125202 , WO2006/085961 , WO2004/024921 , WO2006/074265 .
  • Suitable MCP-1 antagonists are, for instance, C-243 (Telik Inc.); NOX-E36 (Noxxon Pharma AG); AP-761 (Actimis Pharmaceuticals Inc.); ABN-912, NIBR-177 (Novartis AG); CC-11006 (Celgene Corp.); SSR-150106 (Sanofi-Aventis); MLN-1202 (Millenium Pharmaceuticals Inc.); AGI-1067, AGIX-4207, AGI-1096 (AtherioGenics Inc.); PRS-211095, PRS-211092 (Pharmos Corp.); anti-C5a monoclonal antibodies, e.g.
  • neutrazumab G2 Therapies Ltd.
  • AZD-6942 AstraZeneca plc.
  • 2-mercaptoimidazoles Johnson & Johnson
  • TEI-E00526, TEI-6122 Deltagen
  • RS-504393 Roche Holding AG
  • SB-282241, SB-380732, ADR-7 GaxoSmithKline
  • anti-MCP-1 monoclonal antibodies Johnson & Johnson.
  • Combinations of QC-inhibitors with MCP-1 antagonists may be useful for the treatment of inflammatory diseases in general, including neurodegenerative diseases.
  • Combinations of QC-inhibitors with MCP-1 antagonists are preferred for the treatment of Alzheimer's disease.
  • the QC inhibitor is combined with one or more compounds selected from the following group:
  • Such a combination therapy is in particular useful for AD, FAD, FDD and neurodegeneration in Down syndrome as well as atherosclerosis, rheumatoid arthritis, restenosis and pancreatitis.
  • Such combination therapies might result in a better therapeutic effect (less proliferation as well as less inflammation, a stimulus for proliferation) than would occur with either agent alone.
  • At least one compound of formula (I) optionally in combination with at least one of the other aforementioned agents can be used as the active ingredient(s).
  • the active ingredient(s) is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • Injectable suspensions may also prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient(s) necessary to deliver an effective dose as described above.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, from about 0.03 mg to 100 mg/kg (preferred 0.1 - 30 mg/kg) and may be given at a dosage of from about 0.1 - 300 mg/kg per day (preferred 1 - 50 mg/kg per day) of each active ingredient or combination thereof.
  • the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
  • compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of each active ingredient or combinations thereof of the present invention.
  • the tablets or pills of the compositions of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
  • the pharmaceutical composition may contain between about 0.01 mg and 100 mg, preferably about 5 to 50 mg, of each compound, and may be constituted into any form suitable for the mode of administration selected.
  • Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions.
  • Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • liquid forms in suitable flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • suitable suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • tragacanth for example, tragacanth, acacia, methyl-cellulose and the like.
  • methyl-cellulose methyl-cellulose and the like.
  • suitable suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • the compounds or combinations of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds or combinations of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamid-ephenol, or polyethyl eneoxidepolyllysine substituted with palmitoyl residue.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • Compounds or combinations of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of the addressed disorders is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1.000 mg per mammal per day.
  • the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of each active ingredient or combinations thereof for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 300 mg/kg of body weight per day.
  • the range is from about 1 to about 50 mg/kg of body weight per day.
  • the compounds or combinations may be administered on a regimen of 1 to 4 times per day.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • the invention also provides a process for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula (I), optionally in combination with at least one of the other aforementioned agents and a pharmaceutically acceptable carrier.
  • compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.
  • Suitable dosages, including especially unit dosages, of the the compounds of the present invention include the known dosages including unit doses for these compounds as described or referred to in reference text such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31 st Edition page 341 and pages cited therein) or the above mentioned publications.
  • Benzimidazol-5-carbohydrazide (1 eq.) was suspended in dry THF (10 ml). After addition of TEA (1.1 eq.) the respective acid chloride (1.1 eq.) was added dropwise and the reaction was stirred at room temperature for 3 h. The mixture was then quenched with water and extracted with EtOAc (3x25 ml). The combined organic layers were dried over Na 2 SO 4 and evaporated. The remains were redissolved in acetonitrile (10 ml), treated with Lawesson's reagent (1.5 eq.) and heated to reflux for 1 h.
  • N,N -Dicyclohexylcarbodiimide (1 eq.) and the respective carboxylic acid (1 eq.) were dissolved in THF (10 ml) and stirred at room temperature for 1 h.
  • Benzimidazol-5-carbohydrazide (1 eq.) was added and the mixture was stirred at 50°C over night.
  • Lawesson's reagent 1.5 eq.
  • the mixture was quenched by means of sat. NaHCO 3 -solution and extracted with EtOAc (3x25 ml). The combined organic layers were dried over Na 2 SO 4 , evaporated and the residue was purified by semi-preparative HPLC.
  • Benzimidazol-5-carbohydrazide (1 eq.) and the respective carboxylic acid were suspended in acetonitrile (10 ml). Lawesson's reagent (1.5 eq.) and POCl 3 (1.5 eq.) were added and the mixture was heated to reflux over night. After cooling to room temperature, the mixture was basified by means of sat. NaHCO 3 -solution and extracted with EtOAc (3x25 ml). The combined organic layers were dried over Na 2 SO 4 , evaporated and the residue was purified by semi-preparative HPLC.
  • Step 1 Benzimidazol-5-(ethylcarboxiimidate)-dihvdrochloride
  • Step 1 The residue of Step 1 was suspended in dry EtOH (20 ml) and treated with hydrazine-monohydrate (1.5 g; 30 mmol). The mixture was stirred at room temperature for 3 h. The precipitated solid was collected by filtration and washed with a small amount of water. The product was used without further purification. Yield: 0.75 g (51.2 %); MS m/z: 176.4 [M+H] +
  • Benzimidazol-5-carboxylic acid (1.62 g; 10 mmol; 1 eq.) was suspended in toluol (50 ml), treated with SOCl 2 (3.63 ml; 50 mmol; 5 eq.) and heated to reflux over night. The volatiles were evaporated and the remains were taken up with THF (50 ml). After cooling to 0°C 1,8-diazabicyclo[5.4.0]undec-7-en (2.23 ml; 15 mmol; 1.5 eq.) was added carefully.
  • Phenylpropionic acid (0.451 g; 3 mmol; 1eq.) was dissolved in THF (10 ml), treated with Carbonyldiimidazole (0.486 g; 3 mmol; 1 eq.) and stirred at room temperature for 1 h. The mixture was cooled to 0°C and a solution of isocyanoethylacetate (0.393 ml; 3.6 mmol; 1.2 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.34 ml; 9 mmol; 3 eq.) in THF (10 ml) was added dropwise.
  • 3-(2,3-Dimethoxyphenyl propionic acid (0.630 g; 3 mmol; 1 eq.) was dissolved in THF (10 ml), treated with carbonyldiimidazole (0.486 g; 3 mmol; 1 eq.) and stirred at room temperature for 1 h.
  • the mixture was cooled to 0°C and a solution of isocyanoethylacetate (0.393 ml; 3.6 mmol; 1.2 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.34 ml; 9 mmol; 3 eq.) in THF (10 ml) was added dropwise.
  • Benzimidazole-5-carbohydrazide (1 eq.) was suspended in THF (10 ml), treated with the respective isocyanate or isothiocyanate (1 eq.) and heated to reflux for 1 hour. The solvent was removed in vacuo, the remains were taken up with Na 2 CO 3 (5% in H 2 O, 20 ml) and heated to reflux for 3 hours. After cooling to room temperature, the mixture was neutralized by means of 4 N HCl and extracted with EtOAc (3x25 ml). The combined organic layers were dried over Na 2 SO 4 , evaporated and the residue was purified by flash chromatography on silica using a CHCl 3 /MeOH Gradient.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (203mg, .88mmol), 4-phenoxy benzyl amine (350mg, 1.76mmol), acetic acid (5mL) as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (200mg, 0.86mmol), 3-chloro benzyl amine (250mg, 1.73mmol), Acetic acid (5mL) as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (300mg, 1.29mmol), 2, 4-dichloro benzyl amine (0.35mL, 2.60mmol), acetic acid (5mL) as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (300mg, 1.29mmol), 2-chloro-6-flouro benzyl amine (0.35mL, 2.60mmol), acetic acid (5mL) as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (300mg, 1.29mmol), 3, 5-dichloro benzyl amine (0.35mL, 2.60mmol), acetic acid (5mL) as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (300mg, 1.29mmol), 3-chloro-4-flouro benzyl amine (420mg, 2.60mmol), acetic acid (5mL). as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (300mg, 1.29mmol), 2,5-dichloro benzyl amine (0.35mL, 2.60mmol), acetic acid (5mL) as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (300mg, 1.29mmol), 3,4-dichloro benzyl amine (.35mL, 2.60mmol), Acetic acid (5mL) as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (300mg, 1.29mmol), 2-methoxy benzyl amine (0.4mL, 2.60mmol), Acetic acid (5mL) as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (300mg, 1.29mmol), 2,6-dichloro benzyl amine (0.35mL, 2.60mmol), Acetic acid (5mL) as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (300mg, 1.29mmol), 4-triflouromethoxy benzyl amine (0.4mL, 2.60mmol), acetic acid (5mL) as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (300mg, 1.29mmol), 2,3-diflouro benzyl amine (0.3mL, 2.60mmol), acetic acid (5mL) as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (300mg, 1.29mmol), 2,3-dichloro benzyl amine (0.35mL, 2.60mmol), acetic acid (5mL) as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (300mg, 1.29mmol), 2-chloro-5-(trifluoro methyl)-benzyl amine (0.51 mL, 3.25mmol), acetic acid (5mL) as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (300mg, 1.29mmol), 3-chloro-4-methoxy-benzyl amine (445mg, 2.60mmol), acetic acid (5mL) as described above.
  • the compound was synthesized starting from H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide (350mg, 1.51mmol), 4-ethoxy benzyl amine (.570mg, 3.79mmol), acetic acid (5mL) as described above.
  • Example 70 7-(5-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-1,3,4-thiadiazol-2-yl)H-imidazo[12-a]pyridine
  • QC activity was determined from a standard curve of ⁇ -naphthylamine under assay conditions. One unit is defined as the amount of QC catalyzing the formation of 1 ⁇ mol pGlu- ⁇ NA from H-Gln- ⁇ NA per minute under the described conditions.
  • QC was activity determined using H-Gln-AMC as substrate. Reactions were carried out at 30 °C utilizing the NOVOStar reader for microplates (BMG labtechnologies). The samples consisted of varying concentrations of the fluorogenic substrate, 0.1 U pyroglutamyl aminopeptidase (Qiagen) in 0.05 M Tris/HCL, pH 8.0 containing 5 mM EDTA and an appropriately diluted aliquot of QC in a final volume of 250 ⁇ l. Excitation/emission wavelengths were 380/460 nm. The assay reactions were initiated by addition of glutaminyl cyclase. QC activity was determined from a standard curve of 7-amino-4-methylcoumarin under assay conditions. The kinetic data were evaluated using GraFit sofware.
  • This novel assay was used to determine the kinetic parameters for most of the QC substrates.
  • QC activity was analyzed spectrophotometrically using a continuous method, that was derived by adapting a previous discontinuous assay ( Bateman, R. C. J. 1989 J Neurosci Methods 30, 23-28 ) utilizing glutamate dehydrogenase as auxiliary enzyme.
  • Samples consisted of the respective QC substrate, 0.3 mM NADH, 14 mM ⁇ -Ketoglutaric acid and 30 U/ml glutamate dehydrogenase in a final volume of 250 ⁇ l. Reactions were started by addition of QC and persued by monitoring of the decrease in absorbance at 340 nm for 8-15 min.
  • the initial velocities were evaluated and the enzymatic activity was determined from a standard curve of ammonia under assay conditions. All samples were measured at 30 °C, using either the SPECTRAFluor Plus or the Sunrise (both from TECAN) reader for microplates. Kinetic data was evaluated using GraFit software.
  • the sample composition was the same as described above, except of the putative inhibitory compound added.
  • samples contained 4 mM of the respective inhibitor and a substrate concentration at 1 K M .
  • influence of the inhibitor on the auxiliary enzymes was investigated first. In every case, there was no influence on either enzyme detected, thus enabling the reliable determination of the QC inhibition.
  • the inhibitory constant was evaluated by fitting the set of progress curves to the general equation for competitive inhibition using GraFit software.
  • the compounds were analyzed using a gradient at a flow rate of 1 mL/min; whereby eluent (A) was acetonitrile, eluent (B) was water, both containing 0.1 % (v/v) trifluoro acetic acid applying the following gradient:: 0 min - 5 min ⁇ 5% (A), 5 min - 17 min ⁇ 5 - 15% (A), 15 min - 27 min ⁇ 15 - 95% (A) 27 min - 30 min ⁇ 95% (A), Method [B]: 0 min ⁇ 15 min ⁇ 5 - 60 % (A), 15 min - 20 min ⁇ 60 - 95 % (A), 20 min - 23 min ⁇ 95 % (A), Method [C]: 0 min - 20 min ⁇ 5 - 60 % (A), 20 min - 25 min ⁇ 60 - 95 % (A).
  • Matrix-assisted laser desorption/ionization mass spectrometry was carried out using the Hewlett-Packard G2025 LD-TOF System with a linear time of flight analyzer.
  • the instrument was equipped with a 337 nm nitrogen laser, a potential acceleration source (5 kV) and a 1.0 m flight tube.
  • Detector operation was in the positive-ion mode and signals are recorded and filtered using LeCroy 9350M digital storage oscilloscope linked to a personal computer. Samples (5 ⁇ l) were mixed with equal volumes of the matrix solution.
  • DHAP/DAHC For matrix solution DHAP/DAHC was used, prepared by solving 30 mg 2',6'-dihydroxyacetophenone (Aldrich) and 44 mg diammonium hydrogen citrate (Fluka) in 1 ml acetonitrile/0.1% TFA in water (1/1, v/v). A small volume ( ⁇ 1 ⁇ l) of the matrix-analyte-mixture was transferred to a probe tip and immediately evaporated in a vacuum chamber (Hewlett-Packard G2024A sample prep accessory) to ensure rapid and homogeneous sample crystallization.
  • Aldrich 2',6'-dihydroxyacetophenone
  • Fluka diammonium hydrogen citrate
  • a ⁇ -derived peptides were incubated in 100 ⁇ l 0.1 M sodium acetate buffer, pH 5.2 or 0.1 M Bis-Tris buffer, pH 6.5 at 30 °C. Peptides were applied in 0.5 mM [A ⁇ (3-11)a] or 0.15 mM [A ⁇ (3-21)a] concentrations, and 0.2 U QC is added all 24 hours.
  • the assays contained 1 % DMSO.
  • samples are removed from the assay tube, peptides extracted using ZipTips (Millipore) according to the manufacturer's recommendations, mixed with matrix solution (1:1 v/v) and subsequently the mass spectra recorded. Negative controls either contain no QC or heat deactivated enzyme.
  • the sample composition was the same as described above, with exception of the inhibitory compound added (5 mM or 2 mM of a test compound of the invention).
  • Compounds and combinations of the invention may have the advantage that they are, for example, more potent, more selective, have fewer side-effects, have better formulation and stability properties, have better pharmacokinetic properties, be more bioavailable, be able to cross blood brain barrier and are more effective in the brain of mammals, are more compatible or effective in combination with other drugs or be more readily synthesized than other compounds of the prior art.
  • the invention embraces all combinations of preferred and more preferred groups and embodiments of groups recited above.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Reproductive Health (AREA)
  • Cardiology (AREA)
  • Rheumatology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Transplantation (AREA)
  • Oncology (AREA)
  • Psychology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)

Claims (13)

  1. Composé de formule (I) :
    Figure imgb0311
     ou l'un de ses sels pharmaceutiquement acceptables, de ses solvates ou polymorphes, y compris tous ses tautomères et stéréoisomères, où :
    R1 représente un cycle phényle fusionné à un cycle hétéroaryle de 5 chaînons, où R1 est lié au coeur de la formule (I) par l'intermédiaire du cycle phényle ;
    Y représente un groupe hétéroaryle de 5 chaînons choisi parmi les groupes triazolyle, thiadiazolyle, thiazolyle, triazol-one ou triazol-thione ;
    X représente un lieur choisi parmi -(CH2)m-R2, (CH2)n-S-R2, -(CH2)p-O-R2 ou - (CH2)p-SO2-R2 ;
    m représente un nombre entier choisi parmi 1 à 4 ;
    n représente un nombre entier choisi parmi 1 ou 2 ;
    p représente le nombre entier 1 ;
    R2 représente un groupe aryle en C6 à C12, hétéroaryle en C6 à C12 ou carbocyclyle en C3 à C12 ;
    où l'un quelconque des groupes aryle en C6 à C12 et hétéroaryle en C6 à C12 susmentionnés peut être éventuellement substitué par un ou plusieurs groupes choisis parmi les groupes alkyle en C1 à C6, alcényle en C2 à C6, alcynyle en C2 à C6, halogénoalkyle en C1 à C6, -thioalkyle en C1 à C6, -SO-alkyle en C1 à C4, -SO2-alkyle en C1 à C4, alcoxy en C1 à C6-, -O-cycloalkyle en C3 à C8 cycloalkyle en C3 à C8, -SO2-cycloalkyle en C3 à C8 -SO-cycloalkyle en C3 à C6, alcényloxy en C3 à C6-, alcynyloxy en C3 à C6-, -C(O)-alkyle en C1 à C6, -C(O)O-alkyle en C1 à C6, alcoxy en C1 à C6-alkyl en C1 à C6-, nitro, halogéno, halogénoalkyle en C1 à C6, halogénoalcoxy en C1 à C6, cyano, hydroxyle, -C(O)OH, -NH2, -NH-alkyle en C1 à C4, -N(alkyl en C1 à C4)(alkyle en C1 à C4), -C(O)N(alkyl en C1 à C4)(alkyle en C1 à C4), -C(O)NH2, -C(O)NH(alkyle en C1 à C4) et -C(O)NH-(cycloalkyle en C3 à C10);
    et où l'un quelconque des groupes carbocyclyle en C3 à C12 susmentionnés peut être éventuellement substitué par un ou plusieurs groupes choisis parmi les groupes alkyle en C1 à C4, oxo, halogéno et alcoxy en C1 à C4 ;
    ou R2 représente un groupe phényle substitué par un groupe phényle, phényle substitué par un groupe hétéroaryle en C6 à C12 monocyclique, phényle substitué par un groupe phénoxy, phényle substitué par un groupe hétérocyclyle en C3 à C12, phényle substitué par un groupe -O-alkyl en C1 à C4-hétérocyclyle en C3 à C12, phényle substitué par un groupe benzyloxy, phényle substitué par un groupe carbocyclyle en C3 à C12 ou phényle fusionné à un groupe hétérocyclyle en C3 à C12, de telle façon que lorsque Y représente un groupe oxadiazolyle et X représente CH2, R2 représente un groupe autre qu'un groupe phényle substitué par un groupe phénoxy ;
    où l'un quelconque des groupes phényle, benzyloxy et hétéroaryle en C6 à C12 susmentionnés peut être éventuellement substitué par un ou plusieurs groupes choisis parmi les groupes alkyle en C1 à C4, halogéno et alcoxy en C1 à C4,
    et où l'un quelconque des groupes carbocyclyle en C3 à C12 et hétérocyclyle en C3 à C12 susmentionnés peut être éventuellement substitué par un ou plusieurs groupes choisis parmi les groupes méthyle, phényle, oxo, halogéno et alcoxy en C1 à C4 ;
    à condition que le composé de formule (I) soit un composé autre que :
    la 6-(5-(2,3-diméthoxyphénéthyl)-1,3,4-thiadiazol-2-yl)H-imidazol[1,2-a]pyridine ;
    la 6-(5-(4-(méthylthio)phénéthyl)-1,3,4-thiadiazol-2-yl)H-imidazol[1,2-a]pyridine ; ou
    la 6-(5-(2-chloro-3-méthoxyphénéthyl)-1,3,4-thiadiazol-2-yl)H-imidazol[1,2-a]pyridine.
  2. Composé selon la revendication 1, dans lequel R1 représente
    Figure imgb0312
  3. Composé selon les revendications 1 ou 2, dans lequel Y représente un groupe triazolyle, ou thiadiazolyle.
  4. Composé selon l'une quelconque des revendications 1 à 3, dans lequel X représente un lieur choisi parmi - (CH2)m-R2 et-(CH2)n-S-R2.
  5. Composé selon l'une quelconque des revendications 1 à 4, dans lequel R2 représente un groupe aryle en C6 à C12, hétéroaryle en C6 à C12, carbocyclyle en C3 à C12, phényle substitué par un groupe phénoxy ou phényle fusionné à un groupe hétérocyclyle en C3 à C12 ; où l' un quelconque des groupes aryle en C6 à C12, hétéroaryle en C6 à C12, phényle, hétérocyclyle en C3 à C12 et carbocyclyle en C3 à C12 susmentionnés peut être éventuellement substitué par un ou plusieurs groupes tels que définis dans la revendication 1.
  6. Composé selon la revendication 5, dans lequel R2 représente un groupe phényle éventuellement substitué par un ou plusieurs groupes choisis parmi les groupes alkyle en C1 à C6, alcoxy en C1 à C6, -thioalkyle en C1 à C6, halogénoalkyle en C1 à C6, halogénoalcoxy en C1 à C6 ou halogéno ;
    ou R2 représente un groupe pyridyle, qui peut être éventuellement substitué par un ou plusieurs groupes choisis parmi les groupes halogéno, hydroxyle, alkyle en C1 à C6 et alcoxy en C1 à C6 ;
    ou R2 représente un groupe phényle substitué par un groupe 4-phénoxy ;
    ou R2 représente un groupe benzo-1,3-dioxolanyle, 4-méthoxy(benzo-1,3-dioxolanyle), 6-méthoxy(benzo-1,3-dioxolanyle), 2,2-difluoro(benzo-1,3-dioxolanyle) ou benzo-1,4-dioxanyle.
  7. Composé selon l'un quelconque des exemples 1 à 25 et 46 à 89 ou l'un de ses sels pharmaceutiquement acceptables, de ses solvates ou polymères, y compris tous les tautomères et stéréoisomères : 1
    Figure imgb0313
         5-(4-benzyl-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     2
    Figure imgb0314
         5-(4-(3,4-diméthoxybenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     3
    Figure imgb0315
         5-(4-(2-fluorobenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     4
    Figure imgb0316
         5-(4-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     5
    Figure imgb0317
         5-(4-(4-chlorobenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     6
    Figure imgb0318
         5-(4-(3,4-difluorobenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     7
    Figure imgb0319
         5-(4-(4-méthylbenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     8
    Figure imgb0320
         5-(4-(4-méthoxybenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     9
    Figure imgb0321
         5-(4-(2-chlorobenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     10
    Figure imgb0322
         5-(4-(4-phénoxybenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     11
    Figure imgb0323
         5-(4-(3-chlorobenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     12
    Figure imgb0324
         5-(4-(2,4-dichlorobenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     13
    Figure imgb0325
         5-(4-(2-chloro-6-fluoro-benzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     14
    Figure imgb0326
         5-(4-(3,5-dichlorobenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     15
    Figure imgb0327
         5-(4-(3-chloro-4-fluoro-benzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     16
    Figure imgb0328
         5-(4-(2,5-dichlorobenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     17
    Figure imgb0329
         5-(4-(3,4-dichlorobenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     18
    Figure imgb0330
         5-(4-(2-méthoxybenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     19
    Figure imgb0331
         5-(4-(2,6-dichlorobenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     20
    Figure imgb0332
         5-(4-(4-(trifluorométhoxy)-benzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     21
    Figure imgb0333
         5-(4-(2,3-difluorobenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     22
    Figure imgb0334
         5-(4-(2,3-dichlorobenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     23
    Figure imgb0335
         5-(4-(2-chloro-5-(trifluoro-méthyl)benzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]-imidazole     24
    Figure imgb0336
         5-(4-(3-chloro-4-méthoxy-benzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     25
    Figure imgb0337
         5-(4-(4-éthoxybenzyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     46
    Figure imgb0338
         5-(5-phénéthyl-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     47
    Figure imgb0339
         5-(5-(3,4-diméthoxy-phénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     48
    Figure imgb0340
         5-(5-(2,4-diméthoxy-phénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     49
    Figure imgb0341
         5-(5-(2,3-diméthoxy-phénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     50
    Figure imgb0342
         5-(5-(4-(méthylthio)-phénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     51
    Figure imgb0343
         5-(5-(2,4-dichlorophénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     52
    Figure imgb0344
         5-(5-(3-chloro-4-méthoxy-phénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     53
    Figure imgb0345
         5-(5-(4-(trifluorométhyl)-phénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     54
    Figure imgb0346
         5-(5-(2-(benzo[d][1,3]dioxol-5-yl)éthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     55
    Figure imgb0347
         5-(5-(3,4,5-triméthoxy-phénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     56
    Figure imgb0348
         5-(5-(2,5-bis(trifluoro-méthyl)phénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     57
    Figure imgb0349
         5-(5-(2,4-difluorophénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     58
    Figure imgb0350
         5-(5-(3,4-difluorophénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     59
    Figure imgb0351
         5-(5-(3-fluorophénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     60
    Figure imgb0352
         5-(5-(3-méthoxyphénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     61
    Figure imgb0353
         5-(5-(2-méthoxyphénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     62
    Figure imgb0354
         5-(5-(2,5-diméthoxy-phénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     63
    Figure imgb0355
         5-(5-(2-chloro-3-méthoxy-phénéthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     64
    Figure imgb0356
         5-(5-(phénoxyméthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     65
    Figure imgb0357
         5-(5-((phénylthio)méthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     66
    Figure imgb0358
         5-(5-((phénylsulfonyl)-méthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     67
    Figure imgb0359
         5-(5-((3,4-diméthoxyphényl-thio)méthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     68
    Figure imgb0360
         5-(5-((3,4-diméthoxyphényl-sulfonyl)méthyl)-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazole     69
    Figure imgb0361
         7-(5-(2,3-diméthoxy-phénéthyl)-1,3,4-thiadiazol-2-yl)H-imidazo[1,2-a]pyridine     70
    Figure imgb0362
         7-(5-(2-benzo[1,3]dioxol-5-yl)éthyl)-1,3,4-thiadiazol-2-yl)H-imidazo[1,2-a]pyridine     71
    Figure imgb0363
         7-(5-(2-chloro-3-méthoxy-phénéthyl)-1,3,4-thiadiazol-2-yl)H-imidazo[1,2-a]pyridine     72
    Figure imgb0364
         7-(5-(4-méthylthio)-phénéthyl)-1,3,4-thiadiazol-2-yl)H-imidazo[1,2-a]pyridine     73
    Figure imgb0365
         5-(5-phénéthyl-4H-1,2,4-triazol-3-yl)-1H-benzo[d]-imidazole     74
    Figure imgb0366
         5-(5-(3,4-diméthoxy-phénéthyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     75
    Figure imgb0367
         5-(5-(2-chloro-3-méthoxy-phénéthyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole     76
    Figure imgb0368
         5-(2-(3,4-diméthoxy-phénéthyl)thiazol-5-yl)-1H-benzo[d]imidazole     77
    Figure imgb0369
         5-(2-(2-chloro-3-méthoxy-phénéthyl)thiazol-5-yl)-1H-benzo[d]imidazole     78
    Figure imgb0370
         5-(2-(2,3-diméthoxy-phénéthyl)thiazol-5-yl)-1H-benzo[d]imidazole     79
    Figure imgb0371
         5-(2-(2,5-diméthoxy-phénéthyl)thiazol-5-yl)-1H-benzo[d]imidazole     80
    Figure imgb0372
         5-(2-phénéthylthiazol-5-yl)-1H-benzo[d]imidazole     81
    Figure imgb0373
         2-(1H-benzo[d]imidazol-5-yl)-5-phénéthylthiazole     82
    Figure imgb0374
         2-(1H-benzo[d]imidazol-5-yl)-5-(2,3-diméthoxyphénéthyl)-thiazole     83
    Figure imgb0375
         5-(1-phénéthyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]-imidazole     84
    Figure imgb0376
         5-(1-((phénylthio)méthyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazole     85
    Figure imgb0377
         5-(1-(3,4-diméthoxy-phénéthyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazole     86
    Figure imgb0378
         5-(1-(4-méthoxyphénéthyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazole     87
    Figure imgb0379
         5-(1-(3-méthoxyphénéthyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazole     88
    Figure imgb0380
         5-(1H-benzo[d]imidazol-5-yl)-4-benzyl-2H-1,2,4-triazol-3(4H)-one     89
    Figure imgb0381
         5-(1H-benzo[d]imidazol-5-yl)-4-benzyl-2H-1,2,4-triazol-3(4H)-thione
  8. Composé selon l'une quelconque des revendications 1 à 7 pour une utilisation en tant que médicament.
  9. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 7 éventuellement en combinaison avec un ou plusieurs diluants ou supports thérapeutiquement acceptables.
  10. Composition pharmaceutique selon la revendication 9, qui comprend en outre au moins un composé, choisi dans le groupe constitué de neuroprotecteurs, médicaments antiparkinsoniens, inhibiteurs de dépôt de la protéine amyloïde, inhibiteurs de la synthèse de bêta-amyloïde, antidépresseurs, médicaments anxiolytiques, médicaments antipsychotiques et médicaments anti-sclérose en plaques.
  11. Composition pharmaceutique selon la revendication 9 ou 10, qui comprend en outre au moins un composé, choisi dans le groupe constitué d'inhibiteurs du PEP, LiCl, inhibiteurs de la DP IV et des enzymes de type DP IV, inhibiteurs de l'acétylcholinestérase (ACE), amplificateurs de la PIMT, inhibiteurs des bêta-sécrétases, inhibiteurs des gamma-sécrétases, inhibiteurs de l'endopeptidase neutre, inhibiteurs de la phosphodiestérase 4 (PDE-4), inhibiteurs du TNF-alpha, antagonistes des récepteurs muscariniques M1, antagonistes des récepteurs NMDA, inhibiteurs du récepteur sigma-1, antagonistes histaminiques H3, agents immunomodulateurs, agents immunosuppresseurs ou un agent choisi dans le groupe consistant en antegren (natalizumab), Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD 271, adapalène), BAY 361677 (interleukine 4), inhibiteurs des métalloprotéinases matricielles, interféron-tau (trophoblastine) et SAIK-MS.
  12. Composé selon l'une quelconque des revendications 1 à 7 ou composition pharmaceutique selon l'une quelconque des revendications 9 à 11 pour une utilisation dans le traitement d'une maladie choisie dans le groupe constitué de la maladie de Kennedy, le cancer duodénal avec ou sans infection par Helicobacter pylori, le cancer colorectal, le syndrome de Zollinger-Ellison, le cancer gastrique avec ou sans infection par Helicobacter pylori, les affections psychotiques pathogènes, la schizophrénie, la stérilité, les néoplasies, les réponses inflammatoires de l'hôte, le cancer, les métastases malignes, le mélanome, le psoriasis, l'altération des réponses immunitaires humorales et à médiation cellulaire, l'altération de la prise d'aliments, l'altération du sommeil et de l'état de veille, l'altération de la régulation homéostatique du métabolisme énergétique, l'altération de la fonction autonome, l'altération de l'équilibre hormonal ou l'altération de la régulation des liquides corporels, la sclérose en plaques, le syndrome de Guillain-Barré et la polyradiculoneuropathie démyélinisante inflammatoire chronique ;
    ou d'une maladie choisie dans le groupe constitué des troubles cognitifs légers, la maladie d'Alzheimer, la démence familiale de type britannique, la démence familiale de type danois, la neurodégénérescence dans le syndrome de Down et la maladie de Huntington ;
    ou d'une maladie choisie dans le groupe constitué de la polyarthrite rhumatoïde, l'athérosclérose, la pancréatite et la resténose.
  13. Procédé de préparation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 7, qui comprend :
    (a) la préparation d'un composé de formule (I) dans laquelle R1 représente un groupe 1H-benzo[d]imidazolyle à partir d'un composé de formule (II) :
    Figure imgb0382
     dans laquelle X et Y sont tels que définis dans la revendication 1 ;
    (b) la préparation d'un composé de formule (I) dans laquelle Y représente un groupe 1,2,4-triazolyle par réaction d'un composé de formule (III) :
    Figure imgb0383
     dans laquelle R1 est tel que défini dans la revendication 1, avec un composé de formule X-NH2, où X est tel que défini dans la revendication 1 ;
    (c) la préparation d'un composé de formule (I) dans laquelle Y représente un groupe 1,2,4-triazolyle par réaction d'un composé de formule (IV) :
    Figure imgb0384
     dans laquelle R1 est tel que défini dans la revendication 1, avec un composé de formule X-NH2, où X est tel que défini dans la revendication 1 ;
    (e) la préparation d'un composé de formule (I) dans lequel Y représente un groupe 1,3,4-thiadiazolyle à partir d'un composé de formule (VI) :
    Figure imgb0385
     dans laquelle R1 et X sont tels que définis dans la revendication 1 ;
    (f) la préparation d'un composé de formule (I) dans laquelle Y représente un groupe 1,3,4-thiadiazolyle par réaction d'un composé de formule (VII) :
    Figure imgb0386
     dans laquelle R1 est tel que défini dans la revendication 1, avec un composé de formule X-COOH, où X est tel que défini dans la revendication 1 ;
    (g) la préparation d'un composé de formule (I) dans laquelle Y représente un groupe 4H-1,2,4-triazolyle par réaction d'un composé de formule (VIII) :
    Figure imgb0387
     dans laquelle R1 est tel que défini dans la revendication 1, avec un composé de formule X-COOH, où X est tel que défini dans la revendication 1 ;
    (h) la préparation d'un composé de formule (I) dans laquelle Y représente un groupe thiazolyle par réaction d'un composé de formule R1-COOH avec un composé de formule X-CO-CH2-NH2, où R1 et X sont tels que définis dans la revendication 1 ;
    (i) la préparation d'un composé de formule (I) dans laquelle Y représente un groupe 1,2,4-triazol-one ou 1,2,4-triazol-thione à partir d'un composé de formule (IX) :
    Figure imgb0388
     dans laquelle R1 et X sont tels que définis dans la revendication 1 ;
    (j) l'interconversion des composés de formule (I) ; ou
    (k) la déprotection d'un composé de formule (I) qui est protégé.
EP11707395.7A 2010-03-03 2011-03-03 Inhibiteurs de glutaminyl cyclase Active EP2542549B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US30995110P 2010-03-03 2010-03-03
PCT/EP2011/053154 WO2011107530A2 (fr) 2010-03-03 2011-03-03 Nouveaux inhibiteurs

Publications (2)

Publication Number Publication Date
EP2542549A2 EP2542549A2 (fr) 2013-01-09
EP2542549B1 true EP2542549B1 (fr) 2016-05-11

Family

ID=43798321

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11707395.7A Active EP2542549B1 (fr) 2010-03-03 2011-03-03 Inhibiteurs de glutaminyl cyclase

Country Status (5)

Country Link
US (1) US9181233B2 (fr)
EP (1) EP2542549B1 (fr)
JP (1) JP6026284B2 (fr)
ES (1) ES2586231T3 (fr)
WO (1) WO2011107530A2 (fr)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9505728B2 (en) 2012-03-09 2016-11-29 Inception 2, Inc. Triazolone compounds and uses thereof
US8729263B2 (en) 2012-08-13 2014-05-20 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
CN104918922B (zh) 2012-12-20 2017-04-26 因森普深2公司 三唑酮化合物及其用途
US9040712B2 (en) 2013-01-23 2015-05-26 Novartis Ag Thiadiazole analogs thereof and methods for treating SMN-deficiency-related-conditions
EA030631B1 (ru) 2013-07-31 2018-09-28 Новартис Аг 1,4-дизамещенные аналоги пиридазинхинолина и способы лечения состояний, связанных с smn-дефицитом
CN105579440A (zh) 2013-09-06 2016-05-11 因森普深2公司 三唑酮化合物及其应用
WO2016097305A1 (fr) 2014-12-19 2016-06-23 Probiodrug Ag Nouveau procédé permettant la détection de peptides pglu-abêta
DE102015011780A1 (de) 2015-09-16 2017-03-16 Hochschule Anhalt Neue Glutaminylcyclase-lnhibitoren
CN108250196B (zh) * 2016-12-29 2022-12-30 上海汇伦医药股份有限公司 (哌嗪-1-基)-1氢-咪唑并杂芳环化合物的制备方法
PL3634417T3 (pl) 2017-05-17 2023-09-25 Arcus Biosciences, Inc. Pochodne chinazolino-pirazolowe do leczenia chorób związanych z nowotworem
ES2812698T3 (es) 2017-09-29 2021-03-18 Probiodrug Ag Inhibidores de glutaminil ciclasa
EP3521308B1 (fr) 2018-01-31 2024-03-13 Vivoryon Therapeutics N.V. Anticorps humanisés et dé-immunisés
KR20230135378A (ko) * 2022-03-16 2023-09-25 재단법인 대구경북첨단의료산업진흥재단 싸이아다이아졸 화합물 및 이를 포함하는 염증성 질환의 예방 또는 치료용 약학적 조성물

Family Cites Families (562)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5736816A (ja) 1980-08-14 1982-02-27 Toshiba Corp Chodendokoirunoseizohoho
JPS60165712A (ja) 1984-02-08 1985-08-28 パイオニア株式会社 可変調整部品の自動調整方法
JPS6126111A (ja) 1984-07-16 1986-02-05 Shin Meiwa Ind Co Ltd 産業用ロボツト
JPS6137764A (ja) 1984-07-31 1986-02-22 Suntory Ltd 抗プロリルエンドペプチダ−ゼ活性を有する新規生理活性化合物
JPS6152021A (ja) 1984-08-22 1986-03-14 Fujitsu Ltd スケルチ回路
JPS6172439A (ja) 1984-09-18 1986-04-14 Sanyo Electric Co Ltd デ−タ転送方式
DE3684633D1 (de) 1985-04-16 1992-05-07 Suntory Ltd Dipeptid-derivate von fettsaeure, verfahren zu ihrer herstellung, heilmittel, das sie enthaelt und anwendung.
US4873342A (en) 1985-04-16 1989-10-10 Suntory Limited Dipeptide derivative and synthesis and use thereof
JPH0623190B2 (ja) 1985-04-16 1994-03-30 サントリー株式会社 インヒビタ−活性を有するｎ−アシルピロリジン誘導体及びその製法並びに用途
JPS62114957A (ja) 1985-11-13 1987-05-26 Suntory Ltd プロリルエンドペプチダ−ゼ阻害作用を有する新規ピロリジン誘導体およびその製法並びに用途
JPH0714878B2 (ja) 1985-11-14 1995-02-22 サントリー株式会社 ピロリジンアミドを有効成分とするプロリルエンドペプチダーゼ阻害剤
JPH0764834B2 (ja) 1985-11-29 1995-07-12 サントリー株式会社 プロリルエンドペプチダーゼ阻害活性を有する新規ピロリジンアミド誘導体およびその製法並びに用途
US4746669A (en) 1985-12-23 1988-05-24 Merck & Co., Inc. Substituted thiazoles as immunoregulants
CA1320734C (fr) 1986-02-04 1993-07-27 Suntory Limited Derive pyrrolidineamide d'acide acylamine; composition pharmaceutique a base de ce derive
US5198458A (en) 1986-02-04 1993-03-30 Suntory Limited Pyrrolidineamide derivatives of acylamino acid and pharmaceutical composition containing the same
CA1334092C (fr) 1986-07-11 1995-01-24 David John Carini Imidazoles bloquant les recepteurs de l'angiotensine ii
JPS6386485A (ja) 1986-09-30 1988-04-16 Agency Of Ind Science & Technol トンネル型ジヨセフソン接合素子
US5223482A (en) 1986-11-17 1993-06-29 Scios Nova Inc. Recombinant Alzheimer's protease inhibitory amyloid protein and method of use
JPH08806B2 (ja) 1986-11-18 1996-01-10 サントリー株式会社 プロリルエンドペプチダ−ゼ阻害作用を有する新規ピロリジンアミド誘導体
ES2058089T3 (es) 1986-11-20 1994-11-01 Ono Pharmaceutical Co Un procedimiento para la preparacion de un nuevo derivado de prolinal.
US5254550A (en) 1986-11-20 1993-10-19 Ono Pharmaceutical Co., Ltd. Prolinal derivatives and pharmaceutical compositions thereof
JPS63162672A (ja) 1986-12-25 1988-07-06 Ono Pharmaceut Co Ltd 新規なプロリナ−ル誘導体、それらの製造方法およびそれらを含有する抗健忘症剤
EP0275482B1 (fr) 1986-12-29 1993-01-20 Ono Pharmaceutical Co., Ltd. Dérivés de la proline
US5262431A (en) 1986-12-29 1993-11-16 Ono Pharmaceutical Co., Ltd. Prolinal derivatives and pharmaceutical compositions thereof
JPH089591B2 (ja) 1986-12-29 1996-01-31 小野薬品工業株式会社 新規なプロリナール誘導体
EP0277588B1 (fr) 1987-02-04 1993-03-24 Ono Pharmaceutical Co., Ltd. Dérivés du prolinal
JP2528343B2 (ja) 1987-02-04 1996-08-28 小野薬品工業株式会社 新規なプロリナ―ル誘導体
DE3855875T2 (de) 1987-02-23 1997-08-28 Ono Pharmaceutical Co Thiazolidin-Derivate
JPS6442465A (en) 1987-08-07 1989-02-14 Wakunaga Pharma Co Ltd N-acylprolylpyrrolidine derivative, production and use thereof
JP2649237B2 (ja) 1988-03-07 1997-09-03 キッセイ薬品工業 株式会社 チアゾリジン誘導体
US4857524A (en) 1987-08-08 1989-08-15 Kissei Pharmaceutical Co., Ltd. Thiazolidine compounds and therapeutic method
JP2515558B2 (ja) 1987-09-10 1996-07-10 株式会社ヤクルト本社 新規なペプチドおよびそれを有効成分とする抗健忘症剤
CA1339014C (fr) 1987-10-08 1997-03-25 Ronald E. Majocha Anticorps pour peptide a4-amyloide
JPH0742309B2 (ja) 1987-11-30 1995-05-10 キッセイ薬品工業株式会社 チアゾリジン誘導体
JPH01250370A (ja) 1987-12-23 1989-10-05 Zeria Pharmaceut Co Ltd 新規アミノ酸イミド誘導体、製法ならびに用途
US5053414A (en) 1988-04-08 1991-10-01 Ono Pharmaceutical Co., Ltd. Heterocyclic compounds
US5328899A (en) 1988-07-15 1994-07-12 The Salk Institute For Biological Studies NPY peptide analogs
ZA896376B (en) 1988-08-26 1990-05-30 Merrell Dow Pharma Neuropeptide y agonists
ZA896374B (en) 1988-08-26 1990-05-30 Merrell Dow Pharma Neuropeptide y antagonists
JP2531989B2 (ja) 1988-09-14 1996-09-04 吉富製薬株式会社 ピリジン化合物
CA2004028C (fr) 1988-12-08 1998-09-22 Motoki Torizuka Derives condenses de benzene
JPH02207070A (ja) 1989-02-07 1990-08-16 Zeria Pharmaceut Co Ltd アミノ酸イミド誘導体、それを含有する医薬及び該化合物の製造中間体
WO1990012005A1 (fr) 1989-04-13 1990-10-18 Japan Tobacco Inc. Nouveaux derives aminoacides possedant une activite d'inhibiteur de la prolylendopeptidase
AU5525090A (en) 1989-04-14 1990-11-16 Research Foundation For Mental Hygiene, Inc. Monoclonal antibody to amyloid peptide
WO1990012871A1 (fr) 1989-04-14 1990-11-01 Research Foundation For Mental Hygiene, Inc. Anticorps monoclonal sv17-6e10 specifique de la proteine amyloide cerebrovasculaire
CA2018438C (fr) 1989-06-14 2000-08-08 Joseph Alan Finkelstein Acides imidazolyl-alkenoiques
DE3939797A1 (de) 1989-12-01 1991-06-06 Basf Ag Neue vom neuropeptid y abgeleitete peptide
US4985560A (en) 1990-01-12 1991-01-15 American Home Products Corporation Pyridazino(4,5-b)indolizines
DK0443983T3 (da) 1990-02-19 1996-03-18 Ciba Geigy Ag Acrylforbindelser
JPH04211648A (ja) 1990-07-27 1992-08-03 Nippon Kayaku Co Ltd ケト酸アミド誘導体
JPH03255080A (ja) 1990-03-05 1991-11-13 Yoshitomi Pharmaceut Ind Ltd ベンゼン化合物
NZ237476A (en) 1990-03-20 1994-01-26 Sanofi Sa N-substituted heterocyclic compounds and pharmaceutical compositions.
US5073549A (en) 1990-03-22 1991-12-17 Bristol-Myers Squibb Company BU-4164E - A and B, prolyl endopeptidase inhibitors and their methods of use
US4999349A (en) 1990-03-22 1991-03-12 Bristol-Myers Squibb Co. BU-4164E - A and B, prolyl endopeptidase inhibitors
US5196444A (en) 1990-04-27 1993-03-23 Takeda Chemical Industries, Ltd. 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof
EP0536163A1 (fr) 1990-06-04 1993-04-14 Pfizer Inc. Amides de pyrrolidine et de thiazolidine aromatiques
DK0536399T3 (da) 1990-06-07 1996-06-03 Zeria Pharm Co Ltd Hidtil ukendt arylalkanonylaminderivat og lægemiddel indeholdende samme
EP0468469A2 (fr) 1990-07-27 1992-01-29 Japan Tobacco Inc. Dérivés de proline
US5506256A (en) 1990-07-27 1996-04-09 Yoshitomi Pharmaceutical Industries, Ltd. Proline derivatives possessing prolyl endopeptidase-inhibitory activity
JPH05186498A (ja) 1991-12-27 1993-07-27 Japan Tobacco Inc プロリン誘導体
JPH04235162A (ja) 1990-08-09 1992-08-24 Zeria Pharmaceut Co Ltd 新規コハク酸アミド誘導体およびそれを含有する医薬
JPH04208299A (ja) 1990-11-30 1992-07-29 Ajinomoto Co Inc プロリルエンドペプチターゼ阻害ペプチド
IE920540A1 (en) 1991-02-21 1992-08-26 Sankyo Co 1-biphenylmethylimidazole derivatives, their preparation and¹their therapetuic use
US5104880A (en) 1991-05-01 1992-04-14 Mayo Foundation For Medical Education And Research Huperzine a analogs as acetylcholinesterase inhibitors
AU1992592A (en) 1991-05-24 1993-01-08 Pharmavene, Inc. Treatment of drug withdrawal symptoms and drug craving with type b monoamine oxidase inhibitors
US5449750A (en) 1991-06-20 1995-09-12 Snow Brand Milk Products Co., Ltd. Prolyl endopeptidase inhibitors SNA-115 and SNA-115T, and process for the production and productive strain thereof
DE4121975A1 (de) 1991-07-03 1993-01-07 Basf Ag Thermoplastische formmassen auf der basis von polycarbonaten, styrol/acrylnitril-polymerisaten und polyolefinen
AU665207B2 (en) 1991-07-29 1995-12-21 Warner-Lambert Company Quinazoline derivatives as acetylcholinesterase inhibitors
TW226375B (fr) 1991-10-24 1994-07-11 American Home Prod
WO1993012139A1 (fr) 1991-12-19 1993-06-24 Garvan Institute Of Medical Research Nouvelle molecule inhibant la fonction biologique du neuropeptide tyrosine
JPH05301826A (ja) 1991-12-24 1993-11-16 Snow Brand Milk Prod Co Ltd プロリルエンドペプチダーゼ阻害剤
JPH05201970A (ja) 1992-01-24 1993-08-10 Japan Tobacco Inc 新規プロリン誘導体
JP3318622B2 (ja) 1992-05-27 2002-08-26 独立行政法人産業技術総合研究所 プロリルエンドペプチダーゼ阻害剤
GB9212308D0 (en) 1992-06-10 1992-07-22 Ici Plc Therapeutic compositions
GB9213215D0 (en) 1992-06-20 1992-08-05 Wellcome Found Peptides
JPH06116284A (ja) 1992-10-02 1994-04-26 Yamanouchi Pharmaceut Co Ltd 新規ペプチド
DK0664291T3 (da) 1992-10-05 2000-10-30 Ube Industries Pyrimidinforbindelse
US5260286A (en) 1992-10-16 1993-11-09 Japan Tobacco, Inc. 2-piperidinecarboxylic acid derivatives useful as NMDA receptor antagonists
EP0670309A1 (fr) 1992-11-20 1995-09-06 Japan Tobacco Inc. Compose inhibant la prolyle endopeptidase et utilisation pharmaceutique de ce dernier
US5354758A (en) 1992-12-16 1994-10-11 Japan Tobacco Inc. Benzomorphans useful as NMDA receptor antagonists
JPH06192298A (ja) 1992-12-24 1994-07-12 Mitsui Toatsu Chem Inc 新規機能性ペプチド
DE4326465A1 (de) 1993-01-20 1995-02-09 Thomae Gmbh Dr K Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
US5750349A (en) 1993-01-25 1998-05-12 Takeda Chemical Industries Ltd. Antibodies to β-amyloids or their derivatives and use thereof
JPH06234693A (ja) 1993-02-09 1994-08-23 Snow Brand Milk Prod Co Ltd 新規イソテトラセノン系物質及びその製造法
FR2701480B1 (fr) 1993-02-15 1995-05-24 Sanofi Elf Composés à groupe sulfamoyle et amidino, leur procédé de préparation et les compositions pharmaceutiques les contenant.
EP0611769A1 (fr) 1993-02-16 1994-08-24 Merrell Dow Pharmaceuticals Inc. Inhibiteurs d'acétylcholinerase silylés
AU4982293A (en) 1993-03-02 1994-09-26 Fujisawa Pharmaceutical Co., Ltd. Novel heterocyclic compound
FR2702150B1 (fr) 1993-03-03 1995-04-07 Rhone Poulenc Rorer Sa Application de dérivés de 2H-1,2-4-benzothiadiazine-3(4H)-one-1,1-dioxyde comme antagonistes non compétitifs du récepteur NMDA.
FR2703050B1 (fr) 1993-03-24 1995-04-28 Adir Nouveaux dérivés bicycliques azotés, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent.
EP0627400A1 (fr) 1993-06-04 1994-12-07 Merrell Dow Pharmaceuticals Inc. Inhibiteurs aromatiques d'acétylcholinesterase
EP0707490A1 (fr) 1993-06-18 1996-04-24 University Of Cincinnati Antagonistes et agonistes du neuropeptide y
AU6983894A (en) 1993-06-30 1995-01-24 Zeria Pharmaceutical Co., Ltd. Thiazolidine derivative and medicine containing the same
FR2707643B1 (fr) 1993-07-16 1995-08-11 Rhone Poulenc Rorer Sa Dérivés d'imidazo[1,2-a]pyrazine-4-one, leur préparation et les médicaments les contenant.
FR2707645B1 (fr) 1993-07-16 1995-08-11 Rhone Poulenc Rorer Sa Dérivés d'imidazo[1,2-a]pirazine-4-one, leur préparation et les médicaments les contenant.
EP0709373B1 (fr) 1993-07-23 2001-10-17 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Derive de pyrrolidine
FR2711993B1 (fr) 1993-11-05 1995-12-01 Rhone Poulenc Rorer Sa Médicaments contenant des dérivés de 7H-imidazol[1,2-a]pyrazine-8-one, les nouveaux composés et leur préparation.
AU684861B2 (en) 1993-12-02 1998-01-08 Merrell Pharmaceuticals Inc. Prolyl endopeptidase inhibitors
IL111785A0 (en) 1993-12-03 1995-01-24 Ferring Bv Dp-iv inhibitors and pharmaceutical compositions containing them
FR2717805B1 (fr) 1994-03-28 1996-05-10 Rhone Poulenc Rorer Sa Dérivés de 5H-indeno[1,2-b]pyrazine-2,3-dione, leur préparation et les médicaments les contenant .
FR2717811B1 (fr) 1994-03-28 1996-04-26 Rhone Poulenc Rorer Sa Dérivés d'imidazo[1,2-a]pyrazine-4-one, leur préparation et les médicaments les contenant.
FR2717812B1 (fr) 1994-03-28 1996-05-10 Rhone Poulenc Rorer Sa Indeno[1,2-e]pyrazine-4-ones, leur préparation et les médicaments les contenant.
FR2717813B1 (fr) 1994-03-28 1996-05-10 Rhone Poulenc Rorer Sa Dérivés d'imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one, leur préparation et les médicaments les contenant .
JPH07267988A (ja) 1994-03-31 1995-10-17 Yamanouchi Pharmaceut Co Ltd 新規ペプチド
GB9410320D0 (en) 1994-05-24 1994-07-13 Fisons Corp Novel therapeutic method
GB9418443D0 (en) 1994-09-13 1994-11-02 Pfizer Ltd Therapeutic agents
IL115613A0 (en) 1994-10-20 1996-01-19 Lilly Co Eli Bicyclic neuropeptide y receptor antagonists
US6562862B1 (en) 1994-10-20 2003-05-13 Eli Lilly And Company Methods of inhibiting physiological conditions associated with an excess of neuropeptide Y
US5663192A (en) 1994-10-20 1997-09-02 Eli Lilly And Company Heterocyclic neuropeptide Y receptor antagonists
FR2726275B1 (fr) 1994-11-02 1996-12-06 Rhone Poulenc Rorer Sa Spiro heterocycle-imidazo(1,2-a)indeno(1,2-e)pyrazine)-4'- ones, leur preparation et les medicaments les contenants
IL116584A0 (en) 1994-12-29 1996-03-31 Res Dev Foundation Novel flavin adenine dinucleotide analogue inhibitors of monoamine oxidase
US5691368A (en) 1995-01-11 1997-11-25 Hoechst Marion Roussel, Inc. Substituted oxazolidine calpain and/or cathepsin B inhibitors
GB9500601D0 (en) 1995-01-12 1995-03-01 Wellcome Found Modified peptides
US5786180A (en) 1995-02-14 1998-07-28 Bayer Corporation Monoclonal antibody 369.2B specific for β A4 peptide
US5552411A (en) 1995-05-26 1996-09-03 Warner-Lambert Company Sulfonylquinolines as central nervous system and cardiovascular agents
US5635503A (en) 1995-06-07 1997-06-03 Bristol-Myers Squibb Company Dihydropyridine npy antagonists: piperazine derivatives
US5554621A (en) 1995-06-07 1996-09-10 Bristol-Myers Squibb Company Dihydropyridine NPY antagonists: nitrogen heterocyclic derivatives
IL117997A0 (en) 1995-06-07 1996-10-31 Pfizer Neuropeptide Y1 specific ligands
US5668151A (en) 1995-06-07 1997-09-16 Bristol-Myers Squibb Company Dihydropyridine NPY antagonists: piperidine derivatives
JP3727383B2 (ja) 1995-07-31 2005-12-14 月桂冠株式会社 プロリルエンドペプチダーゼ阻害剤
IL120724A0 (en) 1995-09-01 1997-08-14 Lilly Co Eli Indolyl neuropeptide Y receptor antagonists
AU6966696A (en) 1995-10-05 1997-04-28 Warner-Lambert Company Method for treating and preventing inflammation and atherosclerosis
ES2100129B1 (es) 1995-10-11 1998-02-16 Medichem Sa Nuevos compuestos aminopiridinicos policiclicos inhibidores de acetilcolinesterasa, procedimiento para su preparacion y su utilizacion.
DE19544685A1 (de) 1995-11-30 1997-06-05 Thomae Gmbh Dr K Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
DE19544687A1 (de) 1995-11-30 1997-06-05 Thomae Gmbh Dr K Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
DE19544686A1 (de) 1995-11-30 1997-06-05 Thomae Gmbh Dr K Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
AU7692896A (en) 1995-12-01 1997-06-27 Novartis Ag Quinazolin-2,4-diazirines as NPY receptor antagonist
AU7626496A (en) 1995-12-01 1997-06-27 Ciba-Geigy Ag Heteroaryl compounds
WO1997019682A1 (fr) 1995-12-01 1997-06-05 Synaptic Pharmaceutical Corporation Derives aryle sulfonamide et sulfamide, et leurs utilisations
AU7692996A (en) 1995-12-01 1997-06-27 Ciba-Geigy Ag Receptor antagonists
WO1997020821A1 (fr) 1995-12-01 1997-06-12 Novartis Ag Derives heteroaryles
JPH09157253A (ja) 1995-12-12 1997-06-17 Yamanouchi Pharmaceut Co Ltd 新規アミノ酸誘導体
ZA9610736B (en) 1995-12-22 1997-06-27 Warner Lambert Co 2-Substituted piperidine analogs and their use as subtypeselective nmda receptor antagonists
ZA9610741B (en) 1995-12-22 1997-06-24 Warner Lambert Co 4-Substituted piperidine analogs and their use as subtype selective nmda receptor antagonists
ZA9610745B (en) 1995-12-22 1997-06-24 Warner Lambert Co 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists
JP2000501107A (ja) 1996-01-09 2000-02-02 イーライ・リリー・アンド・カンパニー ベンズイミダゾリル神経ペプチドｙ受容体アンタゴニスト
GB9605027D0 (en) 1996-03-09 1996-05-08 Pfizer Ltd Quinoxalinediones
US5662723A (en) 1996-03-22 1997-09-02 Libbey Glass Inc. Apparatus and method for forming a decorative pattern on glassware having an edge
DE69707659T2 (de) 1996-04-12 2002-05-08 Aventis Pharma Inc Isatinderivate als acetylcholinesterase-inhibitoren und analgetika
DE19616486C5 (de) 1996-04-25 2016-06-30 Royalty Pharma Collection Trust Verfahren zur Senkung des Blutglukosespiegels in Säugern
AU3295297A (en) 1996-06-04 1998-01-05 Synaptic Pharmaceutical Corporation Methods of modifying feeding behavior, compounds useful in such methods, and dna encoding a hypothalamic atypical neuropeptide y/peptide yy receptor (y5)
CA2259010A1 (fr) 1996-07-05 1998-01-15 The Wwk Trust Composition pour le traitement des neuropathies peripheriques contenant des antidepresseurs et/ou des inhibiteurs de monoamins-oxidase et/ou de la vitamine b12 et/ou un precurseurou inducteur d'un neurotransmetteur
EP0915859B1 (fr) 1996-07-23 2003-01-02 Neurogen Corporation Derives benzylamine substitues et nouvelle classe de ligands specifiques des neuropeptides y1
JP2000515527A (ja) 1996-07-23 2000-11-21 ニューロジェン・コーポレーション 特定のアミド―およびアミノ―置換ベンジルアミン誘導体；新種の神経ペプチドｙ１特異的リガンド
WO1998003493A1 (fr) 1996-07-23 1998-01-29 Neurogen Corporation Derives benzylamine substitues et nouvelle classe de ligands specifiques des neuropeptides y1
WO1998005337A1 (fr) 1996-08-01 1998-02-12 Cocensys, Inc. Utilisation de ligands de recepteurs gaba et nmda pour le traitement des cephalees de la migraine
WO1998006703A1 (fr) 1996-08-14 1998-02-19 Warner-Lambert Company Derives 2-phenyle benzimidazole en tant qu'antagonistes de mcp-1
EP0984778B1 (fr) 1996-08-23 2002-06-12 Agouron Pharmaceuticals, Inc. Ligands du neuropeptide y
JP3880664B2 (ja) 1996-09-04 2007-02-14 月桂冠株式会社 プロリルエンドペプチダーゼ阻害ペプチド
WO1998010757A2 (fr) 1996-09-11 1998-03-19 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Utilisation d'antagonistes fonctionnels du n-methyl-d-aspartate pour reduire ou prevenir l'ototoxicite induite par l'aminoglucoside
WO1998015647A1 (fr) 1996-10-08 1998-04-16 Novartis Ag Modulation de l'apoptose
FR2754709B1 (fr) 1996-10-23 1999-03-05 Sanofi Sa Composition cosmetique contenant un antagoniste des recepteurs du neuropeptide gamma et alpha 2 antagonistes susceptibles d'etre incorpores dans une telle composition
TW492957B (en) 1996-11-07 2002-07-01 Novartis Ag N-substituted 2-cyanopyrrolidnes
US6011155A (en) 1996-11-07 2000-01-04 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
WO1998030243A1 (fr) 1997-01-08 1998-07-16 Warner-Lambert Company Inhibiteurs d'acetylcholinesterase en combinaison avec des agonistes muscariniques utilises dans le traitement de la maladie d'alzheimer
US20030068316A1 (en) 1997-02-05 2003-04-10 Klein William L. Anti-ADDL antibodies and uses thereof
JP2894445B2 (ja) 1997-02-12 1999-05-24 日本たばこ産業株式会社 Ｃｅｔｐ活性阻害剤として有効な化合物
CA2284001A1 (fr) 1997-03-13 1998-09-17 Keith Tipton Agents cytoprotecteurs comprenant des inhibiteurs de monoamine-oxydase
EP2305709A1 (fr) 1997-04-09 2011-04-06 Intellect Neurosciences, Inc. Anticorps recombinants spécifiques à des fins bêta-amyloïdes, codage ADN et procédés d'utilisation associés
US8173127B2 (en) 1997-04-09 2012-05-08 Intellect Neurosciences, Inc. Specific antibodies to amyloid beta peptide, pharmaceutical compositions and methods of use thereof
DE69808266D1 (de) 1997-04-16 2002-10-31 Arqule Inc Herstellung und verwendung von alpha-ketoamid derivate und anordnunge
JP2001527554A (ja) 1997-05-07 2001-12-25 アルゴス ファーマシューティカル コーポレーション 抗うつ薬とｎｍｄａレセプター拮抗薬とを組み合わせる神経障害痛の治療用組成物及び治療方法
AU7472798A (en) 1997-05-07 1998-11-27 Algos Pharmaceutical Corporation Cox-2 inhibitors in combination with nmda-blockers for treating pain
DK1009732T3 (da) 1997-06-30 2003-09-22 Merz Pharma Gmbh & Co Kgaa 1-Amino-alkylcyclohexan NMDA receptor antagonister
GB9716657D0 (en) 1997-08-07 1997-10-15 Zeneca Ltd Chemical compounds
GB9716879D0 (en) 1997-08-08 1997-10-15 Shire Int Licensing Bv Treatment of attention deficit disorders
WO1999007413A1 (fr) 1997-08-11 1999-02-18 Algos Pharmaceutical Corporation Inhibiteurs de la substance p associes a des inhibiteurs nmda pour traiter la douleur
SE9703376D0 (sv) 1997-09-18 1997-09-18 Astra Ab A new combination
SE9703414D0 (sv) 1997-09-23 1997-09-23 Astra Ab New compounds
US7179892B2 (en) 2000-12-06 2007-02-20 Neuralab Limited Humanized antibodies that recognize beta amyloid peptide
TWI239847B (en) 1997-12-02 2005-09-21 Elan Pharm Inc N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease
US7964192B1 (en) 1997-12-02 2011-06-21 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidgenic disease
CA2819705C (fr) 1998-02-02 2014-07-08 Trustees Of Tufts College Procede de regulation du metabolisme du glucose et reactifs afferents
AU3034299A (en) 1998-03-09 1999-09-27 Fondatech Benelux N.V. Serine peptidase modulators
US6007841A (en) 1998-03-13 1999-12-28 Algos Pharmaceutical Corporation Analgesic composition and method for treating pain
GB9805561D0 (en) 1998-03-16 1998-05-13 Merck Sharp & Dohme A combination of therapeutic agents
US6541208B1 (en) 1998-03-17 2003-04-01 University Of Maryland Biotechnology Institute Diagnostic method for distinguishing HIV-associated dementia from other forms of dementia
DE19812331A1 (de) 1998-03-20 1999-09-23 Merck Patent Gmbh Piperidinderivate
US6054451A (en) 1998-04-21 2000-04-25 Algos Pharmaceutical Corporation Analgesic composition and method for alleviating pain
WO1999057119A1 (fr) 1998-05-04 1999-11-11 Neotherapeutics, Inc. Nouvelle hypoxanthine 9-substituee de type dopamine et methodes d'utilisation
AU3786299A (en) 1998-05-04 1999-11-23 Neotherapeutics, Inc. Novel serotonin-like 9-substituted hypoxanthine and methods of use
WO1999060024A1 (fr) 1998-05-21 1999-11-25 The University Of Tennessee Research Corporation Procede d'elimination d'amyloide a l'aide d'anticorps anti-amyloide
DE19823831A1 (de) 1998-05-28 1999-12-02 Probiodrug Ges Fuer Arzneim Neue pharmazeutische Verwendung von Isoleucyl Thiazolidid und seinen Salzen
DE19828113A1 (de) 1998-06-24 2000-01-05 Probiodrug Ges Fuer Arzneim Prodrugs von Inhibitoren der Dipeptidyl Peptidase IV
DE19828114A1 (de) 1998-06-24 2000-01-27 Probiodrug Ges Fuer Arzneim Produgs instabiler Inhibitoren der Dipeptidyl Peptidase IV
PE20000728A1 (es) 1998-06-26 2000-08-21 Cocensys Inc Heterociclos 4-bencil piperidina alquilsulfoxido y su uso como antagonistas receptores subtipo-selectivo nmda
US6262081B1 (en) 1998-07-10 2001-07-17 Dupont Pharmaceuticals Company Composition for and method of treating neurological disorders
DE19834591A1 (de) 1998-07-31 2000-02-03 Probiodrug Ges Fuer Arzneim Verfahren zur Steigerung des Blutglukosespiegels in Säugern
US6218383B1 (en) 1998-08-07 2001-04-17 Targacept, Inc. Pharmaceutical compositions for the prevention and treatment of central nervous system disorders
IL125809A (en) 1998-08-17 2005-08-31 Finetech Lab Ltd Process and intermediates for production of donepezil and related compounds
IT1304904B1 (it) 1998-09-11 2001-04-05 Eisai Co Ltd Derivati anticolinesterasici per il trattamento delle sindromidolorose funzionali e/o organiche
CA2345767A1 (fr) 1998-10-16 2000-04-27 Paul Leonce Irma De Nijs Therapie visant a ameliorer la cognition
WO2000029023A1 (fr) 1998-11-12 2000-05-25 Algos Pharmaceutical Corporation Utilisation d'une combinaison d'inhibiteurs de cox-2 et de substances bloquant les recepteurs de nmda pour le traitement de la douleur
AU1738800A (en) 1998-11-23 2000-06-13 Bonnie Davis Dosage formulations for acetylcholinesterase inhibitors
WO2000030674A1 (fr) 1998-11-26 2000-06-02 Ferring Bv Agents neuropeptide y-y4 utilises dans le traitement des troubles de la reproduction
ATE306264T1 (de) 1998-12-11 2005-10-15 Bonnie M Davis Verwendung von acetylcholinesterase inhibitoren zur modulierung der hypothalamus-hypophysen- gonadenachse
GB9902453D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902459D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902461D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902455D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902452D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
WO2000056711A1 (fr) 1999-03-23 2000-09-28 Sumitomo Pharmaceuticals Co., Ltd. Compose d'acide indole-2-carboxylique tricyclique utilise comme antagoniste du recepteur nmda
EP1173486A1 (fr) 1999-04-15 2002-01-23 Merck Frosst Canada & Co. Anticorps reconnaissant l'app clivee par les caspases et leurs procedes d'utilisation
US6121311A (en) 1999-04-28 2000-09-19 Japan Tobacco Inc. Method for treating cocainism
MXPA01011321A (es) 1999-05-05 2003-08-01 Johnson & Johnson Neuropeptidos y ligandos de receptores 3a, 4, 5, 9b-tetrahidro-1h-benz(e)indol-2-il amino derivados utiles en el tratamiento de obesidad y otros trastornos.
JP3148739B2 (ja) 1999-05-19 2001-03-26 ドーマー株式会社 プロリルエンドペプチダーゼ阻害剤
PT1409654E (pt) 1999-06-16 2008-11-25 Boston Biomedical Res Inst Controlo imunológico dos níveis de beta-amilóide in vivo
US6107317A (en) 1999-06-24 2000-08-22 Novartis Ag N-(substituted glycyl)-thiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6172081B1 (en) 1999-06-24 2001-01-09 Novartis Ag Tetrahydroisoquinoline 3-carboxamide derivatives
US6110949A (en) 1999-06-24 2000-08-29 Novartis Ag N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6524616B1 (en) 1999-06-25 2003-02-25 Wake Forest University Health Services Compositions and methods for treating or preventing neurodegeneration and cognitive decline and dysfunction associated with alzheimer's disease, aging, other dementia related disorders and estrogen deficiency related conditions
DE19936521A1 (de) 1999-08-06 2001-02-15 Gruenenthal Gmbh Substituierte Pyrrolidin-2,3,4-trion-3-oxim-Derivate
DE19936719A1 (de) 1999-08-06 2001-02-15 Gruenenthal Gmbh Substituierte 1,5-Dihydropyrrol-2-on-Derivate
AU6766800A (en) 1999-08-13 2001-03-13 Trustees Of Columbia University In The City Of New York, The Methods of inhibiting binding of beta-sheet fibril to rage and consequences thereof
EP1078632A1 (fr) 1999-08-16 2001-02-28 Sanofi-Synthelabo Utilisation des inhibiteurs de monoamine oxydases dans la fabrication d'un médicament contre l'obésité
DE19940130A1 (de) 1999-08-24 2001-03-01 Probiodrug Ges Fuer Arzneim Neue Effektoren der Dipeptidyl Peptidase IV zur topischen Anwendung
TWI292316B (en) 1999-10-11 2008-01-11 Sod Conseils Rech Applic Pharmaceutical composition of thiazole derivatives intended to inhibit mao and/or lipidic peroxidation and/or to act as modulators of sodium channels and the use thereof
UA72558C2 (uk) 1999-11-01 2005-03-15 Мерц Фарма Гмбх Унд Ко. Кгаа 1-аміноалкілциклогексанові антагоністи рецептора nmda
WO2001034594A1 (fr) 1999-11-12 2001-05-17 Guilford Pharmaceuticals, Inc. Inhibiteurs de la dipeptidyl peptidase iv; methodes de fabrication et d'utilisation desdits inhibiteurs
GB9928330D0 (en) 1999-11-30 2000-01-26 Ferring Bv Novel antidiabetic agents
AU779875B2 (en) 2000-01-24 2005-02-17 Merck Sharp & Dohme Limited Gamma-secretase inhibitors
EP1254113A1 (fr) 2000-01-24 2002-11-06 Novo Nordisk A/S 2-cyanopyroles et -pyrrolines a substitution n inhibant l'enzyme dpp-iv
EP1255844B1 (fr) 2000-02-03 2007-09-19 Millennium Pharmaceuticals, Inc. Anticorps humanises anti-ccr2 et procedes d'utilisation de ces anticorps
DK1481992T3 (en) 2000-02-24 2017-01-30 Washington Univ St Louis Humanized antibodies which sequester amyloid beta peptide
GB0005251D0 (en) 2000-03-03 2000-04-26 Merck Sharp & Dohme Therapeutic compounds
WO2001066096A2 (fr) 2000-03-06 2001-09-13 Immune Network Ltd. Compositions destinees a la prevention et au traitement de la demence
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
CA2401749A1 (fr) 2000-03-23 2001-09-27 Elan Pharmaceuticals, Inc. Composes et methodes de traitement de la maladie d'alzheimer
US6992081B2 (en) 2000-03-23 2006-01-31 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
GB0008710D0 (en) 2000-04-07 2000-05-31 Merck Sharp & Dohme Therapeutic compounds
JP4150519B2 (ja) 2000-04-13 2008-09-17 エーザイ・アール・アンド・ディー・マネジメント株式会社 １−ベンジルピリジニウム塩を含有してなるアセチルコリンエステラーゼ阻害剤
EA200200952A1 (ru) 2000-04-26 2003-02-27 Уорнер-Ламберт Компани Производные циклогексиламина в качестве селективных антагонистов подтипов nmda-рецепторов
GB0010188D0 (en) 2000-04-26 2000-06-14 Ferring Bv Inhibitors of dipeptidyl peptidase IV
GB0010183D0 (en) 2000-04-26 2000-06-14 Ferring Bv Inhibitors of dipeptidyl peptidase IV
US20010036949A1 (en) 2000-05-09 2001-11-01 Coe Jotham Wadsworth Pharmaceutical composition and method of treatment of diseases of cognitive dysfunction in a mammal
BR0111279A (pt) 2000-06-01 2003-11-04 Warner Lambert Co Derivados da ciclohexilamina como antagonistas para o receptor do nmda seletivo ao subtipo
EP1292581B1 (fr) 2000-06-06 2005-08-10 Warner-Lambert Company LLC Cyclohexalamines bicycliques et utilisation de celles-ci sous forme d'antagonistes du recepteur nmda
JP2004501145A (ja) 2000-06-22 2004-01-15 ファーモス　コーポレイション 向精神作用をもたない新規なカンナビノイド
GB0015488D0 (en) 2000-06-23 2000-08-16 Merck Sharp & Dohme Therapeutic agents
US6713276B2 (en) 2000-06-28 2004-03-30 Scios, Inc. Modulation of Aβ levels by β-secretase BACE2
US6686449B2 (en) 2000-06-30 2004-02-03 Pharmacia & Upjohn Company Mutant presenilin 1 polypeptides
ATE302751T1 (de) 2000-06-30 2005-09-15 Elan Pharm Inc Verbindungen zur behandlung der alzheimerischen krankheit
EP1301187B1 (fr) 2000-07-04 2005-07-06 Novo Nordisk A/S Purine-2,6-diones comme inhibiteurs des enzymes dipeptidyl-peptidase iv (dpp-iv)
GB0016681D0 (en) 2000-07-06 2000-08-23 Merck Sharp & Dohme Therapeutic compounds
US6556971B1 (en) 2000-09-01 2003-04-29 Snap-On Technologies, Inc. Computer-implemented speech recognition system training
AU2001293056A1 (en) 2000-09-25 2002-04-08 Motorwiz, Inc. Model-based machine diagnostics and prognostics using theory of noise and communications
US20020151591A1 (en) 2000-10-17 2002-10-17 Anabella Villalobos Combination use of acetylcholinesterase inhibitors and GABAa inverse agonists for the treatment of cognitive disorders
HU227197B1 (en) 2000-10-24 2010-10-28 Richter Gedeon Nyrt Nmda receptor antagonist carboxylic acid amide derivatives and pharmaceutical compositions containing them
AU2002210747B2 (en) 2000-11-02 2006-06-01 Merck Sharp & Dohme Limited Sulfamides as gamma-secretase inhibitors
US20020150948A1 (en) 2000-11-03 2002-10-17 Gerardo Castillo Antibody PTI-HS7 for treatment of alzheimer's disease and other amyloidoses and parkinson's disease
TWI243162B (en) 2000-11-10 2005-11-11 Taisho Pharmaceutical Co Ltd Cyanopyrrolidine derivatives
PE20020574A1 (es) 2000-12-06 2002-07-02 Wyeth Corp Anticuerpos humanizados que reconocen el peptido amiloideo beta
US6495335B2 (en) 2000-12-07 2002-12-17 Mario Chojkier Compositions and methods for diagnosing alzheimer's disease
US6670364B2 (en) 2001-01-31 2003-12-30 Telik, Inc. Antagonists of MCP-1 function and methods of use thereof
EP2033952B1 (fr) * 2001-03-01 2012-08-29 Shionogi&Co., Ltd. Composés d'hétéroaryle contenant de l'azote exerçant un effet inhibiteur sur l'intégrase du VIH
TWI245761B (en) 2001-03-01 2005-12-21 Telik Inc Antagonists of MCP-1 function and methods of use thereof
EP1436258A4 (fr) 2001-03-08 2005-03-23 Univ Emory Antagonistes du recepteur nmda dependant du ph
US6649196B2 (en) 2001-03-12 2003-11-18 Mayo Foundation For Medical Education And Research Methods of reducing β-amyloid polypeptides
US6815175B2 (en) 2001-03-16 2004-11-09 Cornell Research Foundation, Inc. Anti-amyloid peptide antibody based diagnosis and treatment of a neurological disease or disorder
US6677365B2 (en) 2001-04-03 2004-01-13 Telik, Inc. Antagonists of MCP-1 function and methods of use thereof
US6573287B2 (en) 2001-04-12 2003-06-03 Bristo-Myers Squibb Company 2,1-oxazoline and 1,2-pyrazoline-based inhibitors of dipeptidyl peptidase IV and method
EP1385544B1 (fr) 2001-04-30 2008-09-24 Eli Lilly And Company Anticorps humanises
ES2318006T3 (es) 2001-04-30 2009-05-01 Eli Lilly And Company Anticuerpos humanizados que reconocen el peptido beta-amiloide.
FR2824825B1 (fr) 2001-05-15 2005-05-06 Servier Lab Nouveaux derives d'alpha-amino-acides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
SI20922A (sl) 2001-05-18 2002-12-31 Krka Tovarna Zdravil, D.D., Novo Mesto Monoklonsko protitelo, ki nevtralizira aktivnost katepsina B, in njegove uporabe
US6562783B2 (en) 2001-05-30 2003-05-13 Neurologic, Inc. Phosphinylmethyl and phosphorylmethyl succinic and glutauric acid analogs as β-secretase inhibitors
WO2002098849A2 (fr) 2001-06-01 2002-12-12 Elan Pharmaceuticals, Inc. Hydroxyalkylamines
AU2002344820B2 (en) 2001-06-20 2006-12-14 Merck & Co., Inc. Dipeptidyl peptidase inhibitors for the treatment of diabetes
DE60209348T2 (de) 2001-06-20 2006-10-12 Merck & Co., Inc. Dipeptidylpeptidase-hemmer zur behandlung von diabetes
GB0115517D0 (en) 2001-06-25 2001-08-15 Ferring Bv Novel antidiabetic agents
JP4300108B2 (ja) 2001-06-27 2009-07-22 スミスクライン ビーチャム コーポレーション ジペプチジルペプチダーゼ阻害剤としてのピロリジン類
JP2005500319A (ja) 2001-06-27 2005-01-06 イーラン　ファーマスーティカルズ、インコーポレイテッド アルツハイマー病の治療に有用なβ−ヒドロキシアミン誘導体
RU2003105463A (ru) 2001-06-27 2004-11-27 Пробиодруг Аг (De) Пептидные структуры, пригодные для конкурентного модулирования катализа, осуществляемого дипептидилпептидазой iv
US7183290B2 (en) 2001-06-27 2007-02-27 Smithkline Beecham Corporation Fluoropyrrolidines as dipeptidyl peptidase inhibitors
KR20040015298A (ko) 2001-06-27 2004-02-18 스미스클라인 비참 코포레이션 디펩티딜 펩티다제 억제제로서의 플루오로피롤리딘
DE10154689A1 (de) 2001-11-09 2003-05-22 Probiodrug Ag Substituierte Aminoketonverbindungen
WO2003002595A2 (fr) 2001-06-27 2003-01-09 Probiodrug Ag Nouveaux inhibiteurs de dipeptidylpeptidase iv et leurs utilisations en tant qu'agents anti-cancereux
DE10150203A1 (de) 2001-10-12 2003-04-17 Probiodrug Ag Peptidylketone als Inhibitoren der DPIV
DE60225556D1 (de) 2001-07-03 2008-04-24 Novo Nordisk As Dpp-iv-inhibierende purin-derivative zur behandlung von diabetes
UA74912C2 (en) 2001-07-06 2006-02-15 Merck & Co Inc Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes
CZ2004233A3 (cs) 2001-07-24 2004-12-15 Richter Gedeon Vegyészeti Gyár Rt. Nové amidové sloučeniny karboxylové kyseliny
WO2003012141A1 (fr) 2001-07-31 2003-02-13 Takeda Chemical Industries, Ltd. Procede de recherche/criblage du gene associe a la maladie d'alzheimer
AU2002324582B9 (en) 2001-08-03 2006-02-16 Schering Corporation Novel gamma secretase inhibitors
MXPA04001016A (es) 2001-08-03 2004-05-27 Schering Corp Derivados de sulfonamida como inhibidores de la gamma secretasa.
DE60226036T9 (de) 2001-08-03 2016-09-29 Medical & Biological Laboratories Co., Ltd. ANTIKÖRPER, DER DAS GM1-GANGLIOSID-GEBUNDENE AMYLOID-b-PROTEIN ERKENNT, UND DNA, DIE FÜR DIESEN ANTIKÖRPER CODIERT
AU2002324468A1 (en) 2001-08-17 2003-03-03 Eli Lilly And Company Rapid improvement of cognition in conditions related to abeta
US20040192898A1 (en) 2001-08-17 2004-09-30 Jia Audrey Yunhua Anti-abeta antibodies
WO2003020289A1 (fr) 2001-08-30 2003-03-13 Ortho-Mcneil Pharmaceutical, Inc. Traitement de la demence et des troubles de la memoire par le biais d'anticonvulsifs et d'inhibiteurs de l'acetylcholinesterase
KR20040033048A (ko) 2001-09-14 2004-04-17 미츠비시 웰파마 가부시키가이샤 티아졸리딘 유도체 및 이의 약학적 용도
AU2002331311A1 (en) 2001-09-19 2003-04-01 Novo Nordisk A/S Heterocyclic compounds that are inhibitors of the enzyme dpp-iv
GB0125445D0 (en) 2001-10-23 2001-12-12 Ferring Bv Protease Inhibitors
AU2002359301B2 (en) 2001-10-23 2008-07-03 Comentis, Inc. Beta-secretase inhibitors and methods of use
GB0125446D0 (en) 2001-10-23 2001-12-12 Ferring Bv Novel anti-diabetic agents
US6861440B2 (en) 2001-10-26 2005-03-01 Hoffmann-La Roche Inc. DPP IV inhibitors
CA2504349A1 (fr) 2001-11-02 2003-05-15 Diagenics International Corporation Methodes et compositions d'anticorps monoclonaux specifiques des proteines beta-amyloides
US7304040B2 (en) 2001-11-02 2007-12-04 Kensuke Egashira Suppression of post-transplant arteriosclerosis
US20050208050A1 (en) 2001-11-09 2005-09-22 Gerd Multhaup Compounds for the diagnosis/prevention/treatment of alzheimer's disease
NZ533158A (en) 2001-11-19 2006-09-29 Elan Pharm Inc 3,4-Disubstituted, 3,5-disubstituted and 3,4,5-substituted piperidines and piperazines
CA2466841A1 (fr) 2001-11-21 2003-06-05 New York University Polypeptides immunogenes synthetiques ne formant pas de depots et peptides homologues destines a des repetitions amyloide $g(b), proteine prion, amyline, $g(a)-synucleine, ou polyglutamine pour induction d'une reponse immunitaire a ceux-ci
CA2468192A1 (fr) 2001-11-26 2003-06-05 Trustees Of Tufts College Inhibiteurs peptidomimetiques d'enzymes de clivage post-proline
WO2003048204A1 (fr) 2001-12-06 2003-06-12 Takeda Chemical Industries, Ltd. Gene associe a la maladie d'alzheimer, sa proteine et son utilisation
WO2003051374A2 (fr) 2001-12-17 2003-06-26 New York State Office Of Mental Health SEQUESTRATION DE Aβ DANS LA REGION PERIPHERIQUE EN L'ABSENCE D'AGENTS IMMUNOMODULATEURS COMME APPROCHE THERAPEUTIQUE POUR LE TRAITEMENT OU LA PREVENTION DES MALADIES LIEES A LA BETA-AMYLOIDE
IL162533A0 (en) 2001-12-19 2005-11-20 Atherogenics Inc Chalcone derivatives and their use to treat diseases
JP5153990B2 (ja) 2001-12-21 2013-02-27 シーエスエル、リミテッド 免疫反応性試薬およびサポニンを含有する組成物、およびその使用方法
AU2002360732A1 (en) 2001-12-26 2003-07-24 Guilford Pharmaceuticals Change inhibitors of dipeptidyl peptidase iv
US6727261B2 (en) 2001-12-27 2004-04-27 Hoffman-La Roche Inc. Pyrido[2,1-A]Isoquinoline derivatives
AU2003235799A1 (en) 2002-01-08 2003-07-24 Nordic Bioscience A/S Modulation of iamt (pimt or pcmt) in immune system
EP1467729A1 (fr) 2002-01-18 2004-10-20 The Genetics Company Inc. Inhibiteurs de beta-secretase
CA2473987C (fr) 2002-01-31 2013-11-19 Tel Aviv University Future Technology Development L.P. Peptides, anticorps diriges contre les maladies associees a l'amyloide et procedes utilisant ces peptides et ces anticorps en vue de diagnostiquer et de traiter ces maladies
US20040171614A1 (en) 2002-02-06 2004-09-02 Schering-Plough Corporation Novel gamma secretase inhibitors
TW200302717A (en) 2002-02-06 2003-08-16 Schering Corp Novel gamma secretase inhibitors
CA2474578C (fr) 2002-02-13 2009-08-25 F. Hoffmann-La Roche Ag Nouveaux derives de pyridine et de pyrimidine
RU2285693C2 (ru) 2002-02-13 2006-10-20 Ф.Хоффманн-Ля Рош Аг Производные пиридина и хинолина, способ их получения, фармацевтическая композиция, применение соединений для лечения заболеваний, ассоциированных с dpp-iv
AR038568A1 (es) 2002-02-20 2005-01-19 Hoffmann La Roche Anticuerpos anti-a beta y su uso
HUP0200849A2 (hu) 2002-03-06 2004-08-30 Sanofi-Synthelabo N-aminoacetil-2-ciano-pirrolidin-származékok, e vegyületeket tartalmazó gyógyszerkészítmények és eljárás előállításukra
MY139983A (en) 2002-03-12 2009-11-30 Janssen Alzheimer Immunotherap Humanized antibodies that recognize beta amyloid peptide
DE60316416T2 (de) 2002-03-25 2008-06-26 Merck & Co., Inc. Heterocyclische beta-aminoverbindungen als inhibitoren der dipeptidylpeptidase zur behandlung bzw. prävention von diabetes
JP4405811B2 (ja) 2002-03-29 2010-01-27 エーザイ・アール・アンド・ディー・マネジメント株式会社 （１−インダノン）−（１，２，３，６−テトラヒドロピリジン）誘導体
AU2003226356A1 (en) 2002-04-12 2003-10-27 Ramot At Tel Aviv University Ltd. Prevention of brain inflammation as a result of induced autoimmune response
WO2003089460A1 (fr) 2002-04-19 2003-10-30 The Governing Council Of The University Of Toronto Methodes et compositions immunologiques pour le traitement de la maladie d'alzheimer
AU2003235283A1 (en) 2002-04-24 2003-11-10 Hiroshi Mori Gamma-secretase inhibitors
CN1649845A (zh) 2002-04-26 2005-08-03 先灵公司 蝇蕈碱拮抗剂
AU2003230392A1 (en) 2002-05-17 2003-12-12 Merck And Co., Inc. Beta-secretase inhibitors
WO2003101458A1 (fr) 2002-05-31 2003-12-11 H. Lundbeck A/S Combinaison d'un antagoniste de n-methyl d-aspartate et d'inhibiteurs de l'esterase d'acetylcholine pour le traitement de la maladie d'alzheimer
AU2003232405A1 (en) 2002-06-04 2003-12-19 Pfizer Products Inc. Flourinated cyclic amides as dipeptidyl peptidase iv inhibitors
AU2003233010A1 (en) 2002-06-04 2003-12-19 Pfizer Products Inc. Process for the preparation of 3,3,4,4-tetrafluoropyrrolidine and derivatives thereof
CN100348599C (zh) 2002-06-06 2007-11-14 卫材R&D管理有限公司 新的稠合咪唑衍生物
KR101031964B1 (ko) 2002-06-19 2011-04-29 사이텍 설패이스 스페셜티즈, 에스.에이. 반광성 분체 도장 조성물
US7361665B2 (en) 2002-07-09 2008-04-22 Vertex Pharmaceuticals Incorporated Inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases
JPWO2004007446A1 (ja) 2002-07-10 2005-11-10 アステラス製薬株式会社 新規なアゼチジン誘導体又はその塩
JP4530852B2 (ja) 2002-07-15 2010-08-25 メルク・シャープ・エンド・ドーム・コーポレイション 糖尿病治療のためのピペリジノピリミジンジペプチジルペプチダーゼ阻害剤
TW200410672A (en) 2002-07-19 2004-07-01 Merz Pharma Gmbh & Co Kgaa NMDA receptor antagonists and their use in inhibiting abnormal hyperphosphorylation of microtubule associated protein tau
US7557137B2 (en) 2002-08-05 2009-07-07 Bristol-Myers Squibb Company Gamma-lactams as beta-secretase inhibitors
AR040847A1 (es) * 2002-08-09 2005-04-20 Astrazeneca Ab 1,2,4-oxadiazoles como moduladores de receptores de glutamato metabotropicos, para el tratamiento de desordenes neurologicos y psiquiatricos
CA2496249C (fr) 2002-08-21 2012-01-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, leur production et leur utilisation comme medicament
DE10238477A1 (de) 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Purinderivate, deren Herstellung und deren Verwendung als Arzneimittel
DE10238470A1 (de) 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel
AU2003270643A1 (en) 2002-09-12 2004-04-30 The Regents Of The University Of California Immunogens and corresponding antibodies specific for high molecular weight aggregation intermediates common to amyloids formed from proteins of differing sequence
EP1538207B1 (fr) 2002-09-12 2010-06-02 Juridical Foundation, The Chemo-Sero-Therapeutic Research Institute Anticorps humain anti-mcp-1 humain et fragment d'anticorps correspondant
ES2201929B1 (es) 2002-09-12 2005-05-16 Araclon Biotech, S.L. Anticuerpos policlonales, metodo de preparacion y uso de los mismos.
ATE368647T1 (de) 2002-09-19 2007-08-15 Abbott Lab Pharmazeutische zusammensetzung und ihre verwendung als inhibitoren von der dipeptidyl peptidase iv (dpp-iv)
US20050282871A1 (en) 2002-09-20 2005-12-22 Burrill Ii Leland C 3-(3,5-Disubstituted-4-hydroxyphenyl)propionamide derivatives as cathepsin b inhibitors
US7273889B2 (en) 2002-09-25 2007-09-25 Innovative Drug Delivery Systems, Inc. NMDA receptor antagonist formulation with reduced neurotoxicity
WO2004029629A1 (fr) 2002-09-27 2004-04-08 Janssen Pharmaceutica N.V. Anticorps monoclonaux beta-amyloide n-11 tronques, compositions, methodes et utilisations
JP4487774B2 (ja) 2002-09-30 2010-06-23 萬有製薬株式会社 ２−アミノベンズイミダゾール誘導体
EP1545582A4 (fr) 2002-10-01 2008-09-17 Univ Northwestern Ligands diffusibles derives de l'amyloide beta (addl), substituts d'addl, molecules de liaison aux addl, et leurs utilisations
GB0223039D0 (en) 2002-10-04 2002-11-13 Merck Sharp & Dohme Therapeutic compounds
GB0223038D0 (en) 2002-10-04 2002-11-13 Merck Sharp & Dohme Therapeutic compounds
AU2003275404A1 (en) 2002-10-07 2004-05-04 Merck & Co., Inc. Antidiabetic beta-amino heterocyclic dipeptidyl peptidase inhibitors
AU2003269850A1 (en) 2002-10-08 2004-05-04 Novo Nordisk A/S Hemisuccinate salts of heterocyclic dpp-iv inhibitors
GB0223494D0 (en) 2002-10-09 2002-11-13 Neuropharma Sa Dual binding site acetylcholinesterase inhibitors for the treatment of alzheimer's disease
JP2006519762A (ja) 2002-10-09 2006-08-31 ライナット ニューロサイエンス コーポレイション アミロイドβペプチド及びその組成物に対する抗体を使用して、アルツハイマー病を治療する方法
WO2004037169A2 (fr) 2002-10-18 2004-05-06 Merck & Co., Inc. Inhibiteurs de dipeptidylpeptidase heterocyclique beta-amino destines au traitement ou a la prevention de diabetes
KR100852834B1 (ko) 2002-10-24 2008-08-18 메르츠 파마 게엠베하 운트 코. 카가아 1-아미노시클로헥산 유도체 및 아세틸콜린에스테라제저해제를 포함하는 약학적 제품 및 이를 이용한 복합 치료
US20040082543A1 (en) 2002-10-29 2004-04-29 Pharmacia Corporation Compositions of cyclooxygenase-2 selective inhibitors and NMDA receptor antagonists for the treatment or prevention of neuropathic pain
WO2004041795A1 (fr) 2002-10-30 2004-05-21 Guilford Pharmaceuticals Inc. Nouveaux inhibiteurs de dipeptidyl peptidase iv
WO2004039773A2 (fr) 2002-10-30 2004-05-13 Nordic Bioscience A/S Composes modulant l'activite de gapdh et/ou de l'iamt
GB0225474D0 (en) 2002-11-01 2002-12-11 Merck Sharp & Dohme Therapeutic agents
FR2846667B1 (fr) 2002-11-06 2004-12-31 Pasteur Institut Fragments variables d'anticorps de camelides a chaine unique diriges contre le peptide beta-amyloide 1-42 et leurs applications pour le diagnostic et le traitement des maladies neuroagregatives
ES2278213T3 (es) 2002-11-07 2007-08-01 MERCK & CO., INC. Derivados de fenilamina como inhibidores de la dipeptidilpeptidasa en el tratamiento o la prevencion de la diabetes.
EP1562897B1 (fr) 2002-11-12 2009-09-16 Merck & Co., Inc. Inhibiteurs de beta-secretase phenylcarboxamide utilises dans le traitement de la maladie d'alzheimer
AU2002952946A0 (en) 2002-11-27 2002-12-12 Fujisawa Pharmaceutical Co., Ltd. Dpp-iv inhibitor
EP1578414A4 (fr) 2002-12-04 2007-10-24 Merck & Co Inc Derives de phenylalanine utilises comme inhibiteurs de la dipeptidylpeptisase pour le traitement ou la prevention de diabetes
US7420079B2 (en) 2002-12-09 2008-09-02 Bristol-Myers Squibb Company Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof
WO2004056727A2 (fr) 2002-12-19 2004-07-08 Atherogenics, Inc. Procede de fabrication de derives de chalcone
CA2508947A1 (fr) 2002-12-20 2004-07-15 Merck & Co., Inc. Derives de 3-amino-4-phenylbutanoique acide utilises en tant qu'inhibiteurs de dipeptidyl peptidase pour le traitement ou la prevention du diabete
JP4673833B2 (ja) 2003-01-07 2011-04-20 メルク・シャープ・エンド・ドーム・コーポレイション アルツハイマー病の治療用大環状β−セクレターゼ阻害剤
AU2004206812A1 (en) 2003-01-17 2004-08-05 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
DE10303974A1 (de) 2003-01-31 2004-08-05 Abbott Gmbh & Co. Kg Amyloid-β(1-42)-Oligomere, Verfahren zu deren Herstellung und deren Verwendung
WO2004069162A2 (fr) 2003-01-31 2004-08-19 Merck & Co., Inc. Derives d'acide 3-amino-4-phenylbutanoique utilises comme inhibiteurs de dipeptidyle peptidase pour le traitement ou la prevention du diabete
AU2004209981B2 (en) 2003-02-01 2009-02-26 Janssen Sciences Ireland Uc Active immunization to generate antibodies to soluble A-beta
JP4662914B2 (ja) 2003-02-04 2011-03-30 エフ．ホフマン−ラ ロシュ アーゲー ガンマ−セクレターゼ阻害剤としてのマロンアミド誘導体
WO2004071408A2 (fr) 2003-02-10 2004-08-26 Applied Molecular Evolution, Inc. Molecules de liaison au peptide a$g(b)
WO2004071454A2 (fr) 2003-02-13 2004-08-26 Guilford Pharmaceuticals Inc. Composes d'azetidine substitues servant d'inhibiteurs de dipeptidyl peptidase iv
CA2516259A1 (fr) 2003-02-18 2004-09-02 Roskamp Research, Llc Proprietes anti-angiogeniques et antitumorales des inhibiteurs de beta-secretase et de gamma-secretase
US8663650B2 (en) 2003-02-21 2014-03-04 Ac Immune Sa Methods and compositions comprising supramolecular constructs
WO2004076434A1 (fr) 2003-02-28 2004-09-10 Aic Inhibiteurs de dipeptidyl peptidases
AU2003207881A1 (en) 2003-02-28 2004-09-17 Aic Dipeptidyl peptidase inhibitors
EP1454627A1 (fr) 2003-03-06 2004-09-08 MyoContract Ltd. Dérivés alpha-cétocarbonyliques comme inhibiteurs de la calpaine
WO2004084830A2 (fr) 2003-03-21 2004-10-07 Buck Institute Méthode de traitement de la maladie d'alzheimer
US20040191334A1 (en) 2003-03-24 2004-09-30 Pang-Chui Shaw Use of transhinone derivates as cholinesterase inhibitors in treating related diseases
EP1608317B1 (fr) 2003-03-25 2012-09-26 Takeda Pharmaceutical Company Limited Inhibiteurs de dipeptidyle peptidase
BRPI0409523A (pt) 2003-03-28 2006-04-18 Acadia Pharm Inc método para o tratamento da dor neuropática, método de identificação de um composto e composição farmacêutica
EA200501524A1 (ru) 2003-03-28 2006-06-30 Сентокор, Инк. Антитела против амилоида, композиции, способы и применения
CN1863810B (zh) 2003-04-09 2010-12-01 惠氏公司 [2-(8，9-二氧代-2，6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)烷基]膦酸衍生物及其作为n-甲基-d-天冬氨酸(nmda)受体拮抗剂的应用
GB0308318D0 (en) 2003-04-10 2003-05-14 Merck Sharp & Dohme Therapeutic agents
GB0308382D0 (en) 2003-04-10 2003-05-21 Univ Cambridge Tech Therapeutic methods and means
WO2004089362A1 (fr) 2003-04-11 2004-10-21 Novo Nordisk A/S 2-cyanopyrroles et leurs analogues en tant qu'inhibiteurs de dipeptidylpeptidase-iv (dp-iv)
US7732162B2 (en) * 2003-05-05 2010-06-08 Probiodrug Ag Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
EP1620091B1 (fr) 2003-05-05 2010-03-31 Probiodrug AG Inhibiteurs de glutaminyl-cyclase
WO2004099134A2 (fr) 2003-05-05 2004-11-18 Prosidion Ltd. Inhibiteurs de la dp iv a base de glutaminyle
AU2004237408C9 (en) 2003-05-05 2010-04-15 Probiodrug Ag Medical use of inhibitors of glutaminyl and glutamate cyclases
ES2246177B1 (es) 2003-05-08 2007-03-01 Universidad De Zaragoza. Uso de anticuerpos para el tratamiento de enfermedades amiloideas.
AU2003902260A0 (en) 2003-05-09 2003-05-29 Fujisawa Pharmaceutical Co., Ltd. Dpp-iv inhibitor
DE602004015110D1 (de) 2003-05-13 2008-08-28 Schering Corp Verbrückte n-arylsulfonylpiperidine als gamma-sekretaseinhibitoren
JP2007511467A (ja) 2003-05-14 2007-05-10 タケダ サン ディエゴ インコーポレイテッド ジペプチジルペプチダーゼインヒビター
CA2524531A1 (fr) 2003-05-14 2004-12-02 Merck And Co., Inc. Derives d'acide 3-amino-4-phenylbutanoique en tant qu'inhibiteurs de dipeptidyl peptidase dans le cadre du traitement ou de la prevention du diabete
US7410964B2 (en) 2003-05-16 2008-08-12 Merck Sharp & Dohme Ltd. Cyclohexyl sulphones as gamma-secretase inhibitors
WO2005000216A2 (fr) 2003-05-27 2005-01-06 Forest Laboratories, Inc. Combinaison d'un antagoniste du recepteur nmda et inhibiteur du recaptage de serotonine selectif pour le traitement de la depression et d'autres troubles de l'humeur
PE20050627A1 (es) 2003-05-30 2005-08-10 Wyeth Corp Anticuerpos humanizados que reconocen el peptido beta amiloideo
AU2003902828A0 (en) 2003-06-05 2003-06-26 Fujisawa Pharmaceutical Co., Ltd. Dpp-iv inhibitor
CN1798556A (zh) 2003-06-06 2006-07-05 麦克公司 作为治疗或者预防糖尿病的二肽基肽酶抑制剂的稠合吲哚
AU2003902946A0 (en) 2003-06-12 2003-06-26 Fujisawa Pharmaceutical Co., Ltd. Dpp-iv inhibitor
CA2527806A1 (fr) 2003-06-17 2004-12-29 Merck & Co., Inc. Derives de cyclohexylglycine servant d'inhibiteurs de la dipeptidyl peptidase pour le traitement ou la prevention du diabete
KR100744893B1 (ko) 2003-06-20 2007-08-01 에프. 호프만-라 로슈 아게 Ｄｐｐ-ｉｖ 저해제로서 헥사하이드로피리도아이소퀴놀린
RS52397B (en) 2003-06-20 2013-02-28 F.Hoffmann-La Roche Ag PYRIDO / 2,1-A / ISOCHINOLINE DERIVATIVES AS DPP-IV INHIBITORS
JP5137400B2 (ja) 2003-06-30 2013-02-06 テル アヴィヴ ユニヴァーシティ フューチャー テクノロジー ディヴェロップメント エル．ピー． アミロイド関連疾患を診断および処置するためのペプチド、それに対する抗体、ならびにその使用方法
WO2005004802A2 (fr) 2003-06-30 2005-01-20 Merck & Co., Inc. Inhibiteurs de la beta-secretase a base de n-alkyle phenylcarboxamide pour le traitement de la maladie d'alzheimer
CA2530006A1 (fr) 2003-07-01 2005-01-20 Merck & Co., Inc. Inhibiteurs de la beta-secretase de phenylcarboxylate destines au traitement de la maladie d'alzheimer
WO2005007614A1 (fr) 2003-07-03 2005-01-27 The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services 6011 Inhibiteurs d'oxydase de monoamine
JP2007528862A (ja) 2003-07-16 2007-10-18 アールブイエックス セラピューティクス， インコーポレイテッド ＴＧＦ−βの効果を下方制御するための化合物および方法
EP1671129A1 (fr) 2003-07-21 2006-06-21 Angiogenetics Sweden AB Composes et methodes pour favoriser l'angiogenese, au moyen d'un inhibiteur de la gamma secretase et en inhibant la voie de la gamma secretase
EP1660058A2 (fr) 2003-07-28 2006-05-31 Merz Pharma GmbH & Co. KGaA Utilisation de composes d'1-amino-alkylcyclohexane dans le traitement de l'hypersensibilite a la douleur
WO2005011581A2 (fr) 2003-07-31 2005-02-10 Merck & Co., Inc. Hexahydrodiazepinones utilises en tant qu'inhibiteurs de la dipeptidyl peptidase iv pour le traitement ou la prevention du diabete
US20050124016A1 (en) 2003-08-01 2005-06-09 Enh Research Institute Antibodies specific for toxic amyloid beta protein oligomers
GB0318447D0 (en) 2003-08-05 2003-09-10 Merck Sharp & Dohme Therapeutic agents
US7579357B2 (en) 2003-08-13 2009-08-25 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2005018545A2 (fr) 2003-08-14 2005-03-03 Merck & Co., Inc. Inhibiteurs macrocycliques de la beta-secretase destines au traitement de la maladie d'alzheimer
WO2005018424A2 (fr) 2003-08-18 2005-03-03 Research Foundation For Mental Hygiene, Inc. Anticorps specifiques de la proteine amyloide fibrillaire et procedure permettant de detecter des depots de proteines amyloides fibrillaires
WO2005023762A1 (fr) 2003-09-04 2005-03-17 Abbott Laboratories Derives de pyrrolidine-2-carbonitrile et leur utilisation comme inhibiteurs de la dipeptidyle peptidase-iv (dpp-iv)
WO2005023858A1 (fr) 2003-09-05 2005-03-17 Cellzome Ag Complexes proteiniques associes au traitement de la proteine precurseur amyloide
WO2005030751A2 (fr) 2003-09-08 2005-04-07 Takeda Pharmaceutical Company Limited Inhibiteurs de dipeptidyle peptidase
JP2007505121A (ja) 2003-09-08 2007-03-08 武田薬品工業株式会社 ジペプチジルぺプチダーゼ阻害剤
WO2005025554A2 (fr) 2003-09-09 2005-03-24 Japan Tobacco Inc. Inhibiteur de la dipeptidylpeptidase iv
CA2538220A1 (fr) 2003-09-09 2005-03-24 Takeda Pharmaceutical Company Limited Utilisation d'un anticorps
EP1660533A4 (fr) 2003-09-12 2009-10-21 Univ California Anticorps monoclonaux specifiques a des intermediaires d'agregation de poids moleculaire eleve communs a des amyloides formes a partir de proteines de sequence differente
GB0322140D0 (en) 2003-09-22 2003-10-22 Pfizer Ltd Combinations
EP1667984B1 (fr) 2003-09-24 2011-05-18 Merck Sharp & Dohme Ltd. Inhibiteurs de gamma-secrétase
WO2005032471A2 (fr) 2003-10-03 2005-04-14 Merck & Co., Inc. Inhibiteurs de type benzylether et benzylamino de beta-secretase pour le traitement de la maladie d'alzheimer
BR0318533A (pt) 2003-10-06 2006-09-12 Torrent Pharmaceuticals Ltd azolidinacarbonitrilas e seu uso como inibidores de dpp-iv
ES2548720T3 (es) 2003-10-06 2015-10-20 F. Hoffmann-La Roche Ag Derivados de dibenzoazepina y benzodiazepina sustituidos útiles como inhibidores de la gamma-secretasa
EP1673366A1 (fr) 2003-10-08 2006-06-28 Pfizer, Inc. Composes de 1- 2-(4-hydroxyphenyl)-2-hydroxyethyl|-piperidin-4-ol en tant qu'antagonistes du recepteur du nmda
DK1675578T3 (da) 2003-10-15 2013-08-26 Probiodrug Ag Inhibitorer af glutaminyl- og glutamatcyclaser til behandling af de neurodegenerative sygdomme FBD og FDD
GB0324236D0 (en) 2003-10-16 2003-11-19 Astrazeneca Ab Chemical compounds
WO2005039580A1 (fr) 2003-10-16 2005-05-06 Boehringer Ingelheim International Gmbh Composition pharmaceutique comprenant un inhibiteur de la recapture des neurotransmetteurs de monoamine et un inhibiteur de l'acetylcholinesterase
TW200519105A (en) 2003-10-20 2005-06-16 Lg Life Science Ltd Novel inhibitors of DPP-IV, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
WO2005079779A1 (fr) 2003-10-22 2005-09-01 Merz Pharma Gmbh & Co. Kgaa Utilisation de derives de 1-aminocyclohexane pour modifier le depot de peptides a$g(b) fibrillogenes dans des amyloidopathies
EP1824846A2 (fr) 2003-11-03 2007-08-29 Probiodrug AG Nouveaux composes pour le traitement de troubles neurologiques
CA2541212A1 (fr) 2003-11-04 2005-05-19 Wallace T. Ashton Derives de phenylalanine fusionnes utilises comme inhibiteurs de la dipeptidyl peptidase-iv dans le traitement ou la prevention du diabete
JP4451449B2 (ja) 2003-11-11 2010-04-14 エフ．ホフマン−ラ ロシュ アーゲー ホスフィン酸誘導体、アルツハイマー病の処置のためのベータセクレターゼインヒビタ
ES2524916T3 (es) 2003-11-12 2014-12-15 Sino-Med International Alliance, Inc. Compuestos heterocíclicos de ácido borónico
ATE517861T1 (de) 2003-11-24 2011-08-15 Merck Sharp & Dohme Benzylether und benzylaminoverbindungen als inhibitoren von beta-secretase zur behandlung von alzheimer-krankheit
DE10355304A1 (de) 2003-11-27 2005-06-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 8-(Piperazin-1-yl)-und 8-([1,4]Diazepan-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
UY28650A1 (es) 2003-12-05 2005-02-28 Forest Laboratories Memantina para la prevencion o disminucion de la conducta suicida y para el tratamiento de la depresion mayor asociada con esta conducta
EP1541143A1 (fr) 2003-12-09 2005-06-15 Graffinity Pharmaceuticals Aktiengesellschaft Inhibiteurs de dpp-iv
EP1541148A1 (fr) 2003-12-09 2005-06-15 Graffinity Pharmaceuticals Aktiengesellschaft Inhibiteurs de dpp-iv
WO2005058849A1 (fr) 2003-12-15 2005-06-30 Glenmark Pharmaceuticals Ltd. Nouveaux inhibiteurs de dipeptidyle peptidase iv, leur procede de preparation et compositions les contenant
CA2548849A1 (fr) 2003-12-19 2005-07-21 Merck & Co., Inc. Inhibiteurs de phenylamide et de pyridylamide de la beta-secretase, traitant la maladie d'alzheimer
AU2005205882A1 (en) 2004-01-22 2005-08-04 Neurosearch A/S Pharmaceutical composition comprising a monoamine neurotransmitter re-uptake inhibitor and an N-methyl-D-aspartate (NMDA) receptors antagonist
WO2005072705A1 (fr) 2004-01-29 2005-08-11 Neuromolecular, Inc. Combinaison d'antagoniste de recepteur nmda et d'inhibiteur mao ou gadpf pour le traitement d'affections liees au systeme nerveux central
WO2005075426A1 (fr) 2004-02-03 2005-08-18 Glenmark Pharmaceuticals Ltd. Nouveaux inhibiteurs de dipeptidyle peptidase iv, leur procedes de preparation et compositions en comportant
JP4996926B2 (ja) 2004-02-05 2012-08-08 プロビオドルグ エージー グルタミニルシクラーゼの新規の阻害剤
AU2005215775B2 (en) 2004-02-13 2011-02-03 Neuromolecular, Inc. Combination of a NMDA receptor antagonist and an anti-depressive drug MAO-inhibitor or a GADPH-inhibitor for the treatment of psychiatric conditions
US20050182044A1 (en) 2004-02-17 2005-08-18 Bruinsma Gosse B. Combinatorial therapy with an acetylcholinesterase inhibitor and (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3,-b]indol-5-yl phenylcarbamate
DE502005007196D1 (de) 2004-02-18 2009-06-10 Boehringer Ingelheim Pharma 8-ä3-amino-piperidin-1-ylü-xanthine, deren herstellung und deren verwendung als dpp-iv hemmer
EP1717250A4 (fr) 2004-02-20 2008-10-01 Immuno Biological Lab Co Ltd Anticorps monoclonal et utilisation de celui-ci
AU2005216970B2 (en) 2004-02-23 2011-07-07 Trustees Of Tufts College Inhibitors of dipeptidylpeptidase IV for regulating glucose metabolism
EP1593671A1 (fr) 2004-03-05 2005-11-09 Graffinity Pharmaceuticals AG Inhibiteurs de la DPP-IV
CN1942186B (zh) 2004-03-09 2010-10-06 国家卫生研究院 吡咯烷化合物
CN102127057A (zh) 2004-03-15 2011-07-20 武田药品工业株式会社 二肽基肽酶抑制剂
EP1740172A4 (fr) 2004-03-19 2007-10-10 Axonyx Inc Inhibiteurs d'acetylcholinesterase et antagonistes de n-methyle-d-aspartate utiles dans le traitement de troubles cognitifs
WO2005095339A1 (fr) 2004-03-31 2005-10-13 Pfizer Products Inc. Dicyanopyrrolidines inhibiteurs de la dipeptidyl peptidase iv
WO2005097103A2 (fr) 2004-04-01 2005-10-20 Axys Pharmaceuticals, Inc. Traitement du diabete et du syndrome metabolique au moyen d'inhibiteurs de la cathepsine b
KR20070010144A (ko) 2004-04-05 2007-01-22 쉐링 코포레이션 신규한 감마 세크레타제 억제제
EP1740581B1 (fr) 2004-04-20 2012-08-22 Merck Sharp & Dohme Corp. Composes derives de pyridyle substitues aux positions 2, 4, 6 utiles comme inhibiteurs de la beta-secretase dans le traitement de la maladie d'alzheimer
EP1740559B1 (fr) 2004-04-20 2014-10-15 Merck Sharp & Dohme Corp. Derives de phenyle 1,3,5-substitues utiles comme inhibiteurs de la beta-secretase pour le traitement de la maladie d'alzheimer
WO2005102390A2 (fr) 2004-04-22 2005-11-03 Pfizer Japan, Inc. Combinaisons comprenant des ligands alpha-2-delta et des antagonistes des recepteurs de nmda
US9549895B2 (en) 2004-04-23 2017-01-24 Massachusetts Eye And Ear Infirmary Methods and compositions for preserving the viability of photoreceptor cells
WO2005105998A1 (fr) 2004-04-27 2005-11-10 Juridical Foundation The Chemo-Sero-Therapeutic Research Institute ANTICORPS DE β PEPTIDE ANTIAMYLOÏDE HUMAIN ET FRAGMENT ANTICORPS DE CELUI-CI
EP1756074A4 (fr) 2004-05-04 2010-05-19 Merck Sharp & Dohme Derives de 1,2,4-oxadiazole en tant qu'inhibiteurs de la dipeptidylpeptidase-iv dans le traitement ou la prevention de diabetes
ATE437870T1 (de) 2004-05-12 2009-08-15 Pfizer Prod Inc Prolinderivate und deren verwendung als dipeptidylpeptidase-iv-inhibitoren
JP2007537257A (ja) 2004-05-13 2007-12-20 メルク　エンド　カムパニー　インコーポレーテッド アルツハイマー病の治療用ベータセクレターゼ阻害剤として有用なフェニルカルボキサミド化合物
AU2005247895A1 (en) 2004-05-18 2005-12-08 Merck & Co., Inc. Cyclohexylalanine derivatives as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
EP1598341A1 (fr) 2004-05-21 2005-11-23 Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft Inhibiteurs de DPP-IV
EP1753730A1 (fr) 2004-06-04 2007-02-21 Takeda Pharmaceutical Company Limited Inhibiteurs de la dipeptidyl peptidase
DE602005022871D1 (de) 2004-06-07 2010-09-23 Univ Ramot Verfahren zur passiven immunisierung gegen eine durch amyloidaggregation gekennzeichnete krankheit oder erkrankung mit vermindertem nervenentzündungsrisiko
EP1604989A1 (fr) 2004-06-08 2005-12-14 Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft Inhibiteurs de DPP-IV
EP1604980A1 (fr) 2004-06-08 2005-12-14 Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft Inhibiteurs de DPP-IV
EP1604662A1 (fr) 2004-06-08 2005-12-14 Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft Derivés de la benzyl amine du acide carboxylique (2R) de la 1-[(3R)-Amino-4-(2-fluoro-phenyl)-butyl]-pyrrolidine et composés similaires pour l'utilisation comme inhibiteurs de la peptidase dipeptidyl IV (DPP-IV) pour le traitement de la diabetes mellitus de type 2
WO2005121132A1 (fr) 2004-06-11 2005-12-22 Shionogi & Co., Ltd. Composé hétérocyclique fondu ayant un effet anti-vhc
US7714021B2 (en) 2004-06-15 2010-05-11 Merck & Co., Inc. Pyrrolidin-3-yl compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's disease
GB0413389D0 (en) 2004-06-16 2004-07-21 Astrazeneca Ab Chemical compounds
JP4963671B2 (ja) 2004-06-21 2012-06-27 メルク・シャープ・エンド・ドーム・コーポレイション 糖尿病の治療または予防のためのジペプチジルペプチダーゼ−ｉｖ阻害剤としてのアミノシクロヘキサン
SE0401601D0 (sv) 2004-06-21 2004-06-21 Bioarctic Neuroscience Ab Protofibril specific antibodies and uses thereof
EP1784425A4 (fr) 2004-06-30 2009-02-18 Centocor Inc Anticorps anti-mcp-1, compositions, procedes et utilisations
JP2008505100A (ja) 2004-06-30 2008-02-21 シェーリング　コーポレイション ガンマ−セクレターゼ阻害剤としての置換ｎ−アリールスルホニル複素環アミン
AU2005269940A1 (en) 2004-07-02 2006-02-09 Northwestern University Monolocal antibodies that target pathological assemblies of amyloid beta (Abeta)
US7786163B2 (en) 2004-07-12 2010-08-31 Forest Laboratories Holdings Limited (BM) Constrained cyano compounds
WO2006019965A2 (fr) 2004-07-16 2006-02-23 Takeda San Diego, Inc. Inhibiteurs de la dipeptidyl peptidase
WO2006014638A2 (fr) 2004-07-19 2006-02-09 The General Hospital Corporation Anticorps anti-oligomeres reticules de la proteine $g(b)-amyloide
WO2006008661A2 (fr) 2004-07-19 2006-01-26 Neurochem (International) Limited Methodes diagnostiques d'amylose affectant de multiples organes
ES2355733T3 (es) 2004-07-22 2011-03-30 Schering Corporation Inhibidores de amida beta-secretasa sustituidos.
WO2006014944A1 (fr) 2004-07-28 2006-02-09 Schering Corporation Inhibiteurs de bêta-secrétase macrocycliques
HUP0401523A3 (en) 2004-07-29 2007-05-02 Richter Gedeon Vegyeszet Indole-2-carboxamide derivatives, pharmaceutical compositions containing them and process for producing them
AP2007003890A0 (en) 2004-07-30 2007-02-28 Rinat Neuroscience Corp Antibodies directed against amy-loid-beta peptide and methods using same
EP1623983A1 (fr) 2004-08-05 2006-02-08 Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft Composés hétérocycliques utilisables comme inhibiteurs de DPP-IV
CA2576405A1 (fr) 2004-08-11 2006-02-16 Mitsubishi Chemical Corporation Anticorps et utilisation s'y rapportant
EP1784188B1 (fr) 2004-08-23 2010-07-14 Merck Sharp & Dohme Corp. Derives de triazole accoles inhibiteurs de la dipeptidyl peptidase-iv utilises dans le traitement ou la prevention du diabete
WO2006021409A1 (fr) 2004-08-25 2006-03-02 Santhera Pharmaceuticals (Schweiz) Ag Inhibiteurs d'alpha-ceto carbonyle calpaine
JP2008510759A (ja) 2004-08-25 2008-04-10 サンセラ ファーマシューティカルズ （シュバイツ） アーゲー α−ケトカルボニルカルパイン阻害剤
US7388007B2 (en) 2004-08-26 2008-06-17 Bristol-Myers Squibb Company Gamma-lactams as beta-secretase inhibitors
TWI374935B (en) 2004-08-27 2012-10-21 Pfizer Ireland Pharmaceuticals Production of α-abeta
WO2006029850A1 (fr) 2004-09-14 2006-03-23 The Genetics Company, Inc. Derives d'hydrazone et leur utilisation comme inhibiteurs de la beta-secretase
CA2580265A1 (fr) 2004-09-17 2006-03-30 Comentis, Inc. Composes amino inhibant l'activite de la beta-secretase et methodes d'utilisation
US20080207527A1 (en) 2004-09-17 2008-08-28 Comentis, Inc. Bicyclic Compounds Which Inhibit Beta-Secretase Activity and Methods of Use Thereof
WO2006058064A2 (fr) 2004-11-29 2006-06-01 Merck & Co., Inc. Aminopiperidines fusionnees utilisees comme inhibiteurs de la dipeptidyle peptidase-iv permettant de traiter ou de prevenir le diabete
US20060246075A1 (en) 2004-09-29 2006-11-02 Marc Mercken Anti-amyloid antibodies, compositions, methods and uses
AU2005292134B2 (en) 2004-10-01 2010-12-23 Merck Sharp & Dohme Corp. Aminopiperidines as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
WO2006042103A2 (fr) 2004-10-05 2006-04-20 Axys Pharmaceuticals, Inc. Inhibiteurs reversibles de la cathepsine b
CA2580266A1 (fr) 2004-10-08 2006-04-20 Novartis Ag Combinaison de composes organiques
WO2006040688A2 (fr) 2004-10-12 2006-04-20 Ernir Snorrason Procede pour traiter des maladies de peau
EP1804794B1 (fr) 2004-10-13 2013-07-31 Merck Sharp & Dohme Corp. Composés de spiropiperidine utilisés comme inhibiteurs de beta-secretase en vue du traitement de la maladie d'alzheimer
US20090004302A1 (en) 2004-10-15 2009-01-01 Biopharmacopae Design International Inc. Methods and Therapeutic Compositions Comprising Plant Extracts for the Treatment of Cancer
EP2465872A3 (fr) 2004-10-25 2012-12-19 Merck Sharp & Dohme Corporation Anticorps anti-ADDL et leurs utilisations
AU2005299808B2 (en) 2004-10-25 2009-08-20 Novartis Ag Combination of DPP-IV inhibitor, PPAR antidiabetic and metformin
JPWO2006046644A1 (ja) 2004-10-28 2008-05-22 三光純薬株式会社 アルツハイマー病の検定方法及び診断試薬
EP1807396B1 (fr) 2004-10-29 2013-06-26 Merck Sharp & Dohme Corp. Composes de 2-aminopyridine utiles comme inhibiteurs de la beta-secretase pour le traitement de la maladie d'alzheimer
AU2005306701A1 (en) 2004-11-17 2006-05-26 Merck & Co., Inc. Macrocyclic tertiary amine beta-secretase inhibitors for the treatment of Alzheimer's disease
CA2587256A1 (fr) 2004-11-23 2006-06-01 Merck & Co., Inc. Inhibiteurs de l'aminopyridyle de la beta-secretase macrocyclique permettant de traiter la maladie d'alzheimer
US8394837B2 (en) 2004-11-23 2013-03-12 Merck, Sharp & Dohme, Corp. 2,3,4,6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease
EP1827385B1 (fr) 2004-11-23 2013-03-27 Adamas Pharmaceuticals, Inc. Composition pharmaceutique contenant memantine dans une forme à liberation prolongée pour le tratiement de dementia
EP2623099A1 (fr) 2004-11-24 2013-08-07 Neuromolecular Pharmaceuticals, Inc Composition et procédé de traitement d'une maladie neurologique
AU2005311511A1 (en) 2004-11-30 2006-06-08 F. Hoffmann-La Roche Ag Substituted benzoquinolizines as DPP-IV inhibitors for the treatment of diabetes
US20080139458A1 (en) 2004-12-03 2008-06-12 Jay Gregory D Methods of Treatment For Injured or Diseased Joints
US20060240486A1 (en) 2004-12-15 2006-10-26 Johnson-Wood Kelly L Immunoprecipitation-based assay for predicting in vivo efficacy of beta-amyloid antibodies
JP2008523815A (ja) 2004-12-15 2008-07-10 エラン ファーマ インターナショナル リミテッド 認知の改善における使用のためのヒト化アミロイドβ抗体
EP1838349A1 (fr) 2004-12-15 2007-10-03 Neuralab, Ltd. ANTICORPS AMYLOIDE beta UTILISES AFIN D'AMELIORER LA COGNITION
WO2006066049A2 (fr) 2004-12-15 2006-06-22 Neuralab Limited Anticorps humanises reconnaissant le peptide beta amyloide
BRPI0519585A2 (pt) 2004-12-20 2009-02-25 Hoffmann La Roche compostos de fàrmula i; processo para a fabricaÇço de compostos de fàrmula i; composiÇÕes farmacÊuticas; mÉtodo para o tratamento e/ou profilaxia de doenÇas que estço associadas com a dpp-iv e usos destes compostos
US7411093B2 (en) 2004-12-20 2008-08-12 Hoffman-La Roche Inc. Aminocycloalkanes as DPP-IV inhibitors
JP2008524331A (ja) 2004-12-21 2008-07-10 武田薬品工業株式会社 ジペプチジルペプチダーゼ阻害剤
WO2006071274A2 (fr) 2004-12-23 2006-07-06 Voyager Pharmaceutical Corporation Acetate de leuprolide et inhibiteurs de l'acetylcholinesterase ou antagonistes des recepteurs nmda pour le traitement de la maladie d'alzheimer
EP1831172B1 (fr) 2004-12-28 2009-02-18 Council of Scientific and Industrial Research Esters d'acide carbamique quinoline-6-yle substitues utiles en tant qu'inhibiteurs de l'acetylcholinesterase
CN101098700A (zh) 2005-01-06 2008-01-02 默克公司 治疗炎性疾病的药物组合疗法和药用组合物
US7820674B2 (en) 2005-01-19 2010-10-26 Merck, Sharp & Dohme Corp. Aminomethyl beta-secretase inhibitors for the treatment of alzheimer's disease
CA2589860A1 (fr) 2005-01-24 2006-08-03 Amgen Inc. Anticorps anti-amyloide humanise
TW200640529A (en) 2005-02-28 2006-12-01 Thomas Christian Lines Composition for treating mental health disorders
US20080194698A1 (en) 2005-03-07 2008-08-14 Michael Hermanussen Nmda Receptor Antagonists in the Medical Intervention of Metabolic Disorders
CN101137736A (zh) 2005-03-09 2008-03-05 柯尼卡美能达医疗印刷器材株式会社 稀土类激活的碱土类金属氟化卤化物辉尽性荧光体、及使用该荧光体的放射线图像转换板
ES2259270B1 (es) 2005-03-09 2007-11-01 Consejo Superior De Investigaciones Cientificas Metodo de diagnostico in vitro de la enfermedad de alzheimer mediante un anticuerpo monoclonal.
US7745470B2 (en) 2005-03-10 2010-06-29 Bristol-Myers Squibb Company Isophthalates as beta-secretase inhibitors
FR2883285B1 (fr) 2005-03-17 2007-05-18 Sanofi Aventis Sa Sel besylate de la 7-(2-(4-(3-trifluoromethyl-phenyl) -1,2,3,6-tetrahudro-pyrid-1-yl)ethyl) isoquinoleine, sa preparation et son utilisation en therapeutique
ES2318918B1 (es) 2005-04-01 2010-02-16 Biotherapix Molecular Medicines, S.L.U. Anticuerpos humanos con capacidad de union al peptido beta-amiloide y sus aplicaciones.
CN101166523A (zh) 2005-04-27 2008-04-23 诺瓦提斯公司 治疗动脉粥样硬化的方法
PE20061323A1 (es) 2005-04-29 2007-02-09 Rinat Neuroscience Corp Anticuerpos dirigidos contra el peptido amiloide beta y metodos que utilizan los mismos
PE20110071A1 (es) 2005-05-19 2011-01-31 Centocor Inc Anticuerpos anti-mcp-1, composiciones y metodos
WO2006137354A1 (fr) 2005-06-21 2006-12-28 Medical & Biological Laboratories Co., Ltd. Anticorps avec effet inhibiteur sur la formation de fibrilles amyloïdes
JP2008545008A (ja) * 2005-06-30 2008-12-11 プロシディオン・リミテッド Ｇｐｃｒアゴニスト
EP2808032B1 (fr) 2005-12-12 2018-08-01 AC Immune S.A. Anticorps specifiques pour a beta possédant des propriétés thérapeutiques
NO346055B1 (no) 2005-12-12 2022-01-24 Ac Immune Sa Antigen konstruksjon, vaksinesammensetning og fremgangsmåte for produksjon derav.
GB0704100D0 (en) 2006-03-17 2007-04-11 Vodafone Plc Improvements in an ehspa architecture
MX2009000476A (es) 2006-07-14 2009-01-28 Ac Immune Sa Anticuerpo humanizado contra beta amiloide.
WO2008016123A1 (fr) 2006-08-03 2008-02-07 Takeda Pharmaceutical Company Limited INHIBITEUR DE LA GSK-3β
EP2079466B1 (fr) * 2006-09-29 2014-01-15 GlaxoSmithKline LLC Composes de l'indole substitue
EP2091945B1 (fr) 2006-11-09 2014-01-15 Probiodrug AG Nouveaux inhibiteurs de la glutaminyl-cyclase
EP2089383B1 (fr) 2006-11-09 2015-09-16 Probiodrug AG Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
DK2086960T3 (da) 2006-11-09 2014-06-10 Probiodrug Ag Nye inhibitorer af glutaminylcyclase.
ATE554085T1 (de) * 2006-11-30 2012-05-15 Probiodrug Ag Neue inhibitoren von glutaminylcyclase
CN101790526A (zh) 2007-06-08 2010-07-28 雅培制药有限公司 用作激酶抑制剂的5-杂芳基取代的吲唑化合物
WO2008157273A1 (fr) * 2007-06-14 2008-12-24 Smithkline Beecham Corporation Composés chimiques
WO2009051705A1 (fr) 2007-10-18 2009-04-23 Merck & Co., Inc. 1,2,4-oxadiazoles substitués et leurs analogues comme modulateurs des récepteurs cb2, utiles dans le traitement de la douleur et de maladies respiratoires et non respiratoires
US8415353B2 (en) * 2008-03-04 2013-04-09 Merck Sharp & Dohme Corp. Amino-quinoxaline and amino-quinoline compounds for use as adenosine A2a receptor antagonists
CN102741270B (zh) * 2009-09-28 2015-07-22 英特穆恩公司 C型肝炎病毒复制的环肽抑制剂

Also Published As

Publication number Publication date
JP6026284B2 (ja) 2016-11-16
US20110224259A1 (en) 2011-09-15
US9181233B2 (en) 2015-11-10
ES2586231T3 (es) 2016-10-13
JP2013521260A (ja) 2013-06-10
WO2011107530A2 (fr) 2011-09-09
EP2542549A2 (fr) 2013-01-09
WO2011107530A3 (fr) 2011-11-10

Similar Documents

Publication Publication Date Title
EP2865670B1 (fr) Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
EP2542549B1 (fr) Inhibiteurs de glutaminyl cyclase
US7803810B2 (en) Inhibitors
EP2091948B1 (fr) Nouveaux inhibiteurs de glutaminylcyclase
EP2142513B1 (fr) Dérivés de nitrovinyl-diamine en tant que inhibiteurs de la glutaminyl-cyclase
EP2142536B1 (fr) Dérivés d'aminopyrimidine utilisés comme inhibiteurs de la glutaminyl cyclase
EP2545047B9 (fr) Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
EP2160380B1 (fr) Dérivés de cyano-guanidine utilisés comme inhibiteurs de la glutaminyl cyclase
EP2344157B1 (fr) Nouveaux inhibiteurs
EP2142515B1 (fr) Derives de nitrovinyl-diamine en tant que inhibiteurs de la glutaminyl-cyclase
EP2686313B1 (fr) Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
EP2146968A1 (fr) Dérivés d'urée utilisés comme inhibiteurs de la glutaminyl cyclase
EP2560953B1 (fr) Inhibiteurs de glutaminyl cyclase

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20120919

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20150120

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20151009

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 798572

Country of ref document: AT

Kind code of ref document: T

Effective date: 20160515

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602011026404

Country of ref document: DE

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

Effective date: 20160728

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: BRAUNPAT BRAUN EDER AG, CH

REG Reference to a national code

Ref country code: NL

Ref legal event code: FP

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2586231

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20161013

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160811

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160812

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160912

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602011026404

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 7

26N No opposition filed

Effective date: 20170214

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170303

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 8

REG Reference to a national code

Ref country code: CH

Ref legal event code: PCAR

Free format text: NEW ADDRESS: HOLEESTRASSE 87, 4054 BASEL (CH)

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170303

REG Reference to a national code

Ref country code: AT

Ref legal event code: UEP

Ref document number: 798572

Country of ref document: AT

Kind code of ref document: T

Effective date: 20160511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20110303

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160511

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160911

REG Reference to a national code

Ref country code: BE

Ref legal event code: PD

Owner name: VIVORYON THERAPEUTICS N.V.; DE

Free format text: DETAILS ASSIGNMENT: CHANGE OF OWNER(S), CHANGE OF LEGAL ENTITY; FORMER OWNER NAME: VIVORYON THERAPEUTICS AG

Effective date: 20211026

Ref country code: BE

Ref legal event code: HC

Owner name: VIVORYON THERAPEUTICS AG; DE

Free format text: DETAILS ASSIGNMENT: CHANGE OF OWNER(S), CHANGE OF OWNER(S) NAME; FORMER OWNER NAME: PROBIODRUG AG

Effective date: 20211026

REG Reference to a national code

Ref country code: NL

Ref legal event code: PD

Owner name: VIVORYON THERAPEUTICS N.V.; DE

Free format text: DETAILS ASSIGNMENT: CHANGE OF OWNER(S), CHANGE OF LEGAL ENTITY; FORMER OWNER NAME: VIVORYON THERAPEUTICS AG

Effective date: 20211202

Ref country code: NL

Ref legal event code: HC

Owner name: VIVORYON THERAPEUTICS AG; DE

Free format text: DETAILS ASSIGNMENT: CHANGE OF OWNER(S), CHANGE OF OWNER(S) NAME; FORMER OWNER NAME: PROBIODRUG AG

Effective date: 20211202

REG Reference to a national code

Ref country code: ES

Ref legal event code: PC2A

Owner name: VIVORYON THERAPEUTICS N.V.

Effective date: 20220110

REG Reference to a national code

Ref country code: AT

Ref legal event code: HC

Ref document number: 798572

Country of ref document: AT

Kind code of ref document: T

Owner name: VIVORYON THERAPEUTICS AG, DE

Effective date: 20211215

REG Reference to a national code

Ref country code: DE

Ref legal event code: R081

Ref document number: 602011026404

Country of ref document: DE

Owner name: VIVORYON THERAPEUTICS N.V., DE

Free format text: FORMER OWNER: VIVORYON THERAPEUTICS AG, 06120 HALLE, DE

Ref country code: DE

Ref legal event code: R081

Ref document number: 602011026404

Country of ref document: DE

Owner name: VIVORYON THERAPEUTICS N.V., DE

Free format text: FORMER OWNER: PROBIODRUG AG, 06120 HALLE, DE

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230517

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20230414

Year of fee payment: 13

Ref country code: CH

Payment date: 20230402

Year of fee payment: 13

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20240319

Year of fee payment: 14

Ref country code: NL

Payment date: 20240320

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20240318

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20240321

Year of fee payment: 14

Ref country code: GB

Payment date: 20240322

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20240329

Year of fee payment: 14

Ref country code: FR

Payment date: 20240319

Year of fee payment: 14

Ref country code: DK

Payment date: 20240321

Year of fee payment: 14

Ref country code: BE

Payment date: 20240320

Year of fee payment: 14